CN101228135A - Pyridazinone derivatives as thyroid hormone receptor agonists - Google Patents
Pyridazinone derivatives as thyroid hormone receptor agonists Download PDFInfo
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Abstract
Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as obesity, hyperlipidemia, hypercholesterolemia and diabetes and other related disorders and diseases, and may be useful for other diseases such as NASH, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer and other disorders and diseases related thereto.
Description
The present invention relates to novel ligands for thyroid receptor, be specifically related to the pyridazinone analogue of formula (I)
Wherein:
A is O, CH
2, S, SO or SO
2
X and Y be selected from independently of one another Br, Cl and-CH
3
R
1Be selected from:
-(CH
2)
nCOOH；
-OCH
2COOH；
-NHC(＝O)COOH；
-NHCH
2COOH；
With
Z is a hydrogen, or-C ≡ N;
R
2It is the low alkyl group that contains 1 to 4 C atom;
R
3Be hydrogen or low alkyl group;
N is 1 or 2;
P is 1 or 2;
Or its medicinal salt or ester.
The invention still further relates to the method for these compounds of preparation, these compounds can be used for treating metabolic trouble as obesity, hyperlipidaemia, hypercholesterolemia and diabetes, and can be used for other illness and disease such as NASH (NA fatty liver (nonalcoholic steatohepatitis)), fatty degeneration of liver, atherosclerosis, cardiovascular disorder, hypothyroidism, thyroid carcinoma and associated conditions and disease.The all files that following institute quotes or relies on all is combined in this by reference clearly.
Triiodothyronine is for normal growth and growth and to keep metabolic balance be crucial (Paul M.Yen, physiology comment (Physiological reviews)), 81 (3) volumes: 1097-1126 page or leaf (2001)).The cyclical level of Triiodothyronine is closely regulated by the Feedback mechanism in hypothalamus/hypophysis/Tiroidina (HPT) axle.Cause hypothyroidism or hyperthyroid thyroid function to clearly illustrate that, Triiodothyronine is to heart function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle and behavior performance far-reaching influence.
Triiodothyronine is produced by Tiroidina and is secreted in the recycle system with following two kinds different forms: 3,5, and 3 ', 5 '-four-iodo-L-thyronine (T4) and 3,5,3 '-three-iodo-L-thyronine (T3).Although T4 is by Tiroidina excretory principal mode, T3 is a form more active on the physiology.T4 takes off the iodine enzyme by tissue specificity and is converted to T3, tissue specificity take off the iodine enzyme be present in the institute in a organized way in, but mainly in liver and kidney.The biological activity of Triiodothyronine is by Thyroid Hormone Receptors (TRs) mediation (M.A.Lazar, internal secretion comment (Endocrine Reviews), 14 volumes: 348-399 page or leaf (1993)).TR belongs to the superfamily that is known as nuclear receptor.TR forms heterodimer with the retinoid acceptor of taking on part-inductive transcription factor.TR has ligand binding domains, DNA binding domains and N-terminal structural domain, and by with the DNA responsive element and with various nuclears altogether-interaction of activator and altogether-repressor and regulatory gene is expressed.Thyroid Hormone Receptors is derived from two genes that separate, α and β.These different gene products produce their acceptors separately of various ways by the RNA processing of difference.Main thryoid receptor isoform is α 1, α 2, β 1 and β 2.Thyroid Hormone Receptors α 1, β 1 and β 2 are in conjunction with Triiodothyronine.Show, the Thyroid Hormone Receptors hypotype at them for can be different aspect the contribution of special physiological response.Nearest studies show that, TR β 1 is regulating TRH (throtropin releasing hormone) and regulating playing an important role on of Triiodothyronine in liver.TR β 2 is at (Abel etc., Journal of Clinical Investigation (J.Clin.Invest.), 104 volumes: 291-300 page or leaf (1999)) of playing a major role aspect the adjusting TSH (thyrotropin).TR β 1 is at (B.Gloss etc., incretology (Endocrinology), 142 volumes: 544-550 page or leaf (2001) of playing an important role aspect the adjusting heart rate; C.Johansson etc., U.S.'s physiology magazine (Am.J.Physiol.), 275 volumes: R640-R646 page or leaf (1998)).
If side effect can minimize or eliminate, then some effects of Triiodothyronine can have treatment benefit (Paul M.Yen physiology comment (Physiological Reviews), 81 (3) volumes: 1097-1126 page or leaf (2001); Paul Webb, expert's viewpoint of drug research (Expert Opin.Investig.Drugs), 13 (5) volumes: 489-500 page or leaf (2004)).For example, Triiodothyronine increases metabolic rate, oxygen consumption and heat release.Thereby reduction body weight.Reducing body weight will have beneficial effect to the obese patient by improving with fat relevant common morbidity, and can have beneficial effect for the obese patient's who suffers from diabetes B glycemic control.
The beneficial effect of another of Triiodothyronine in treatment is to reduce serum low-density LP (LDL) (Eugene Morkin etc., molecule and cell Cardiology magazine (Journal of Molecularand Cellular Cardiology), 37 volumes: 1137-1146 page or leaf (2004)).Have been found that, hyperthyroidism and low total serum are cholesterol-associated, this increases the liver ldl receptor expression owing to Triiodothyronine and stimulates metabolism (J.J.Abrams etc., lipid research magazine (J.Lipid Res.), 22 volumes: 323-38 page or leaf (1981)) of cholesterol to bile acide.Hypothyroidism is relevant with hypercholesterolemia again, and known Triiodothyronine alternative medicine has reduced total cholesterol (M.Aviram etc., clinical biochemical (Clin.Biochem.), 15 volumes: 62-66 page or leaf (1982); J.J.Abrams etc., lipid research magazine (J.Lipid Res.), 22 volumes: 323-38 page or leaf (1981)).In animal model, Triiodothyronine has demonstrated to have to be increased the HDL cholesterol and improves the beneficial effect of LDL to the transformation efficiency of HDL by the expression that increases apo A-1, apo A-1 is one of main Apo of HDL (Gene C.Ness etc., biochemical pharmacology (Biochemical Pharmacology), 56 volumes: 121-129 page or leaf (1998); G.J.Grover etc., incretology (Endocrinology), 145 volumes: 1656-1661 page or leaf (2004); G.J.Grover etc., Proc.Natl.Acad.Sci.USA, 100 volumes: 10067-10072 page or leaf (2003)).By its effect to LDL and HDL cholesterol, possible is that Triiodothyronine can also reduce the danger of atherosclerosis and other cardiovascular disorder.The sickness rate of atherosclerotic blood vessel disease is directly related with the LDL cholesterol levels.In addition, evidence suggests that Triiodothyronine reduces lipoprotein (a), a kind of important risk factor, its in the atherosclerotic, raise (Paul Webb, expert's viewpoint of drug research (Expert Opin.Investig.Drugs), 13 (5) volumes: 489-500 page or leaf (2004); DeBruin etc., clinical endocrine metabolism magazine (J.Clin.Endo.Metab.), 76 volumes: pp.121-126 page or leaf (1993)).
In view of fat and morbidity altogether, diabetes, the sickness rate of metabolism syndrome and atherosclerotic blood vessel disease is fashion trend and rises, and highly needs to treat the application of compound of these diseases.So far, the therepic use of naturally occurring Triiodothyronine is subjected to the restriction of the adverse side effect relevant with hyperthyroidism, particularly Cardiovascular Toxicity.
Therefore, carried out effort with the synthetic thyroid hormone analogs that has the Thyroid Hormone Receptors beta selective of increase and/or organize selective action.This Triiodothyronine stand-in can produce the suitable decline of body weight, lipid, cholesterol and lipoprotein, influence (the A.H.Underwood etc. that the normal function of cardiovascular function or hypothalamus/hypophysis/hypothalamic pituitary thyroidal axis had reduction, nature (Nature), 324 volumes: 425-429 page or leaf (1986), G J.Grover etc., PNAS, 100 volumes: 10067-10072 page or leaf (2003); G.J.Grover, incretology (Endocrinology), 145 volumes: 1656-1661 page or leaf (2004); Yi-lin Li etc., PCT International Application No. WO 9900353 (1999); Thomas S.Scanlan etc., PCT International Application No. WO 9857919 (1998); Keith A.Walker etc., U.S. Patent number 5,284,971 (1994); Mark D.Erion etc., PCT International Application No. WO 2005051298 (2005); Malm Johan, up-to-date medicinal design (Current Pharmaceutical Design), 10 (28) volumes: 3525-3532 page or leaf (2004); Expert's viewpoint of patient treatment (Expert Opin.Ther.Patents), 14 volumes: 1169-1183 page or leaf (2004); Thomas S.Scalan, the up-to-date viewpoint of medicament research and development (CurrentOpinion in Drug Discovery﹠amp; Development), 4 (5) volumes: 614-622 page or leaf (2001); PaulWebb, expert's viewpoint of drug research (Expert Opinion on Investigational Drugs), 13 (5) volumes: 489-500 page or leaf (2004)).
Avoid hyperthyroidism and hypothyroid ill effect to keep the exploitation of thyroid hormone analogs of the beneficial effect of Triiodothyronine will open the following disease patient's of treatment new approach simultaneously: metabolic trouble such as obesity, hyperlipidaemia, hypercholesterolemia, diabetes and other illness and disease such as fatty degeneration of liver and NASH, atherosclerosis, cardiovascular disorder, hypothyroidism, thyroid carcinoma, thyroid disease, and associated conditions and disease.
The previous pyridazinone compound different (Teruomi etc., agricultural and biological chemistry (Agricultural and Biological Chemistry), 38 (6) volume: the 1169-76 (1974) of disclosing with the The compounds of this invention structure; P.D.Leeson etc., pharmaceutical chemistry magazine (J.Med.Chem.), 32 volumes: 320-326 page or leaf (1989); European patent application EP 188351 (1986); Damien JohnDunnington, PCT International Application No. WO 9702023 (1997); With European patent application EP 728482 (1996)).
Therefore, based on this background, the beneficial effect that still needs to have Triiodothyronine is avoided the novel Triiodothyronine stand-in of ill effect simultaneously again, for example, and new pyridazinone Triiodothyronine stand-in.
Should be appreciated that the term purpose of Cai Yonging is to describe specific embodiment, is not intended to limit herein.In addition, although similar or be equivalent to that those any method, device and material described herein all can be used for implementing or test the present invention, description is preferable methods, device and material now.
The term of Shi Yonging " alkyl " expression herein, for example, side chain or non-side chain, ring-type or acyclic, saturated or undersaturated (for example alkenyl or alkynyl) alkyl, it can be substituted also can be unsubstituted.Under the cyclic situation, alkyl is preferably C
3To C
12, more preferably C
4To G
10, more preferably C
4To C
7Under acyclic situation, alkyl is preferably C
1To C
10, more preferably C
1To C
6, more preferably methyl, ethyl, propyl group (n-propyl or sec.-propyl), butyl (normal-butyl, isobutyl-or the tertiary butyl) or amyl group (comprising n-pentyl and isopentyl), more preferably methyl.Therefore, should be understood that herein the term " alkyl " that uses comprises the cycloalkynyl radical of cycloalkenyl group, cycloalkynyl radical and replacement of cycloalkyl, cycloalkenyl group, the replacement of alkyl (side chain or non-side chain), the alkyl (side chain or non-side chain) that replaces, alkenyl (side chain or non-side chain), the alkenyl (side chain or non-side chain) that replaces, alkynyl (side chain or non-side chain), the alkynyl (side chain or non-side chain) that replaces, cycloalkyl, replacement.
The term of Shi Yonging " low alkyl group " expression herein, for example, side chain or non-side chain, ring-type or acyclic, saturated or undersaturated (for example alkenyl or alkynyl) alkyl, wherein said cyclic low-grade alkyl is C
5, C
6Or C
7, wherein said non-annularity low alkyl group is C
1, C
2, C
3, C
4, C
5Or C
6, preferred 1 to 4 carbon atom.Typical low alkyl group comprises methyl, ethyl, propyl group (n-propyl or sec.-propyl), butyl (normal-butyl, isobutyl-or the tertiary butyl), amyl group and hexyl.Therefore, should understand, the term of Shi Yonging " low alkyl group " comprises herein, for example, and low alkyl group (side chain or non-side chain), low-grade alkenyl (side chain or non-side chain), low-grade alkynyl (side chain or non-side chain), low-grade cycloalkyl, lower alkenyl ring and rudimentary cycloalkynyl radical.When being connected to another functional group, the low alkyl group of Shi Yonging can be a divalence herein, for example, and-low alkyl group-COOH.The low alkyl group of preferably acyclic, side chain or non-side chain.
R at formula (I)
2The position, low alkyl group has 1 to 4 carbon atom.Preferred R
2It is the low alkyl group that contains 3 carbon atoms.Be more preferably sec.-propyl.
The term of Shi Yonging " aryl " expression herein, for example, replace or unsubstituted isocyclic aromatic group, as phenyl or naphthyl, perhaps replace or unsubstituted containing more than one, a preferred heteroatomic heteroaromatic group is as pyridyl, pyrryl, furyl, thienyl, thiazolyl, isothiazolyl oxazolyl isoxazolyl oxadiazole base, thiadiazolyl group, pyrazolyl, imidazolyl, triazolyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, indyl, indazolyl, quinolyl, quinazolyl, benzimidazolyl-, benzothiazolyl, benzoisoxazole base and benzisothiazole base.
Alkyl and aryl can be replacements or unsubstituted.Under situation about replacing, there are for example 1 to 3 substituting group, preferred 2 substituting groups usually.Substituting group can comprise, for example: carbon-containing group such as alkyl, aryl, aralkyl (for example replacing and unsubstituted phenyl, replacement and unsubstituted benzyl); Halogen atom and halogen-containing group such as haloalkyl (for example trifluoromethyl); Oxy radical is as alcohol (hydroxyl for example, hydroxyalkyl, aryl (hydroxyl) alkyl), ether (alkoxyl group for example, aryloxy, alkoxyalkyl, aryloxy alkyl), aldehyde (for example formaldehyde), ketone (alkyl-carbonyl for example, the alkyl-carbonyl alkyl, aryl carbonyl, aromatic yl alkyl carbonyl, the aromatic carbonyl alkyl), acid (carboxyl for example, carboxyalkyl), acid derivative such as ester (alkoxy carbonyl for example, alkoxy carbonyl alkyl, the alkyl-carbonyl oxygen base, alkyl-carbonyl oxygen base alkyl), acid amides (aminocarboxyl for example, single-or two-alkyl amino-carbonyl, the aminocarboxyl alkyl, single-or two-alkyl amino alkyl carbonyl, aromatic yl aminocarbonyl), carbamate (alkoxycarbonyl amino for example, aryloxy (arloxy) carbonylamino, aminocarboxyl oxygen base, single-or two-alkyl amino carbonyl oxy, aromatic yl aminocarbonyl oxygen base) and urea (for example single-or two-alkyl amino-carbonyl amino or aromatic yl aminocarbonyl amino); Nitrogen-containing group such as amine (for example amino, single-or two-alkylamino, aminoalkyl group, list-or two-alkylamino alkyl), trinitride, nitrile (for example cyano group, cyano group alkyl), nitro; Sulfur-containing group such as mercaptan, thioether, sulfoxide and sulfone (for example alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkylthio alkyl, alkyl sulphinyl alkyl, alkyl sulphonyl alkyl, arylthio, aryl sulfonyl kia, aryl sulfonyl, arylthio alkyl, aryl sulfonyl kia alkyl, aryl sulfonyl alkyl); With contain more than one, a preferred heteroatomic heterocyclic group (thienyl for example, furyl, pyrryl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl oxazolyl oxadiazole base, thiadiazolyl group, aziridinyl, the azetidine base, pyrrolidyl, pyrrolinyl, imidazolidyl, imidazolinyl, pyrazolidyl, tetrahydrofuran base, pyranyl, the pyrans ketone group, pyridyl, pyrazinyl, pyridazinyl, piperidyl (piperidyl), six hydrogen azepine _ bases, piperazinyl, morpholinyl, sulphur naphthyl (thianaphthyl), benzofuryl, isobenzofuran-base, indyl, the oxyindole base, pseudoindoyl, indazolyl, indolinyl, the 7-azaindolyl, benzopyranyl, the tonka bean camphor base, isocoumarinyl, quinolyl, isoquinolyl, 1,5-phthalazinyl (naphthridinyl), the cinnolines base, quinazolyl, pyridopyridine base benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, the isochroman base, 2 base and carbolinyl).
Low alkyl group can be replacement or unsubstituted, preferably unsubstituted.Under situation about replacing, there are for example 1 to 3 substituting group, preferred 2 substituting groups usually.
The term of Shi Yonging " alkoxyl group " expression herein, for example, alkyl-O-, and " alkyloyl " expression, for example, alkyl-CO-.Alkoxy substituent or the substituting group that contains alkoxyl group can be replaced by for example more than one alkyl.
The term of Shi Yonging " halogen " expression herein, for example, fluorine, chlorine, bromine or iodine group, preferred chlorine or bromine group, more preferably cl radical.
" pharmaceutically useful " is as acceptable and nontoxic basically for the object of particular compound administration on the expression pharmacology such as pharmaceutically useful carrier, vehicle.
" pharmaceutical salts " is meant conventional acid salt or base addition salt, and these salt have kept the biological effectiveness of formula I compound and character and have been to be formed by suitable organic or inorganic acid or organic or inorganic alkali.The example of acid salt comprises derived from those of mineral acid, described mineral acid example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, thionamic acid, phosphoric acid and nitric acid, and derived from organic acid those, described organic acid such as tosic acid, Whitfield's ointment, methylsulfonic acid, oxalic acid, succsinic acid, citric acid, oxysuccinic acid, lactic acid, fumaric acid etc.The example of base addition salt comprises derived from ammonium, potassium, sodium and quaternary ammonium hydroxide those of tetramethylammonium hydroxide for example.With medical compounds (that is, medicine) chemical modification salify is technique known, and it is used to attempt to improve the character that comprises physics or chemical stability, for example, and the water absorbability of compound, flowability or solvability.Referring to, for example, H.Ansel etc., " pharmaceutical dosage form and delivery system (Pharmaceutical Dosage Forms and Drug Delivery Systems) ", (the 6th edition, 1995), 196 and the 1456-1457 page or leaf.
" medicinal ester " is meant the compound of the conventional esterification of the formula I compound that contains carboxyl, this ester kept the biopotency of formula I compound and character and in vivo (in organism) be dissociated into corresponding active carboxylic acid.In the present invention, for example, at R
1Be-(CH
2)
nCOOH ,-OCH
2COOH ,-NHC (=O) COOH or-NHCH
2Under the situation of COOH, can there be ester.The example of the ester group of (in this case, hydrolysis) one-tenth corresponding carboxylic acid of dissociating in vivo is those of wherein hydrogen quilt-low alkyl group replacement, and described-low alkyl group is optional by for example replacement such as heterocycle, cycloalkyl.The example of the lower alkyl esters that replaces be wherein low alkyl group replaced by tetramethyleneimine, piperidines, morpholine, N methyl piperazine etc. those.By dissociated group can be in vivo, for example, ethyl, morpholino ethyl and diethylamino ethyl.Related to the present invention ,-CONH
2Also be considered to ester, because-NH
2Can be decomposed in vivo and replace, form corresponding carboxylic acid with hydroxyl.
Relate to the example of the ester that is used for the delivering drugs compound and the more information visible " former medicine design (Design of Prodrugs) " of purposes, Bundgaard H. edits (Elsevier, 1985).Also referring to, H.Ansel etc., " pharmaceutical dosage form and delivery system (Pharmaceutical Dosage Forms and DrugDelivery Systems) ", (the 6th edition, 1995), 108-109 page or leaf; Krogsgaard-Larsen etc., " medicinal design and exploitation textbook (Textbook ofDrug Design and Development) ", (second edition, 1996), 152-191 page or leaf.
More specifically, the present invention relates to formula (I) compound:
Wherein:
A is O, CH
2, S, SO or SO
2
X and Y be selected from independently of one another Br, Cl and-CH
3
R
1Be selected from:
-(CH
2)
nCOOH；
-OCH
2COOH；
-NHC(＝O)COOH；
-NHCH
2COOH；
With
Z is a hydrogen, or-C ≡ N;
R
2It is low alkyl group;
R
3Be hydrogen or low alkyl group;
N is 1,2 or 3;
P is 1 or 2;
Or its medicinal salt or ester.
Formula (I) compound is preferred separately, and its physiologically acceptable salt is preferred separately and its medicinal ester is preferred separately, and its Chinese style (I) compound is particularly preferred.
Formula (I) compound can have more than one asymmetric C or S atom, and therefore can perhaps exist with the optical pure compound form with the form of mixtures of mixture of enantiomers, steric isomer.
Preferred aforesaid formula (I) compound is those, wherein each Br naturally of X and Y.Other preferred compound is those, wherein each Cl naturally of X and Y.Also preferred compound is those, wherein X and Y each naturally-CH
3In addition, preferred X is Cl, and Y is-CH
3
Preferred aforesaid formula (I) compound is those, wherein R
1Be selected from:
-(CH
2)
nCOOH；
-OCH
2COOH；
-NHC (=O) COOH; With
-NHCH
2COOH; And
Their ester.
Preferred R wherein
1Be-(CH
2)
nCOOH.Preferred n is 1.Other preferred compound is those, wherein R
1Be-NHC (=O) COOH.Other preferred compound is those, wherein R
1Be:
More preferably R wherein
1Be
Preferred Z is CN.
In formula (I) compound, as mentioned above, preferred R
2It is the low alkyl group that contains 1 to 4 C atom.More preferably R
2It is the low alkyl group that contains 1 to 3 C atom.Other preferred aforesaid formula (I) compound is those, wherein R
3Be CH
3
Particularly preferred aforesaid formula (I) compound is
Or its medicinal salt or ester.
Another particularly preferred formula as defined above (I) compound is
Or its pharmaceutical salts.
Another particularly preferred formula as defined above (I) compound is
Or its medicinal salt or ester.
Another particularly preferred formula as defined above (I) compound is
Or its medicinal salt or ester.
Another particularly preferred formula as defined above (I) compound is
Or its medicinal salt or ester.
Another particularly preferred formula as defined above (I) compound is
Or its medicinal salt or ester.
Preferred compound as defined above, it has corresponding to R
1Ester group, this ester group is-(=O) COOR, wherein the ester group corresponding to described " R " is NH to NHC
2
Particularly preferred formula as defined above (I) compound is to be selected from following those:
[4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-3,5-dimethyl-phenyl]-acetate,
[3-chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-5-methyl-phenyl]-acetate,
[3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate,
[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate,
3-[3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-propionic acid,
[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl amino]-acetate,
N-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-the oxalyl amino acid,
2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile,
2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-2H-[1,2,4] triazine-3, the 5-diketone,
[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate,
[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate,
2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile,
2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-[1,2,4] triazine-3, the 5-diketone,
[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate,
[3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate,
2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene [1,2,4] triazine-6-nitrile,
[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-acetate,
[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-sulfinyl)-phenyl]-acetate,
[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-acetate,
2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile,
2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-2H-[1,2,4] triazine-3, the 5-diketone and
2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile,
Or its medicinal salt or ester.
The compound that should be understood that general formula of the present invention (I) can be derived at the functional group place, to obtain transforming back in vivo the derivative of parent compound.
As mentioned above, have been found that novel cpd of the present invention is a thyroid hormone analogs.Therefore, compound of the present invention can be used for treating and/or preventing the disease of being regulated by thyroid hormone analogs, metabolic trouble particularly, as obesity, hyperlipidaemia hypercholesterolemia and diabetes, and can be used for other disease such as NASH (NA fatty liver), atherosclerosis, cardiovascular disorder, hypothyroidism, thyroid carcinoma and associated conditions and disease.The obese patient is that weight index is the people more than 25.
Therefore the present invention also relates to pharmaceutical composition, and it comprises compound and pharmaceutical carrier and/or assistant agent as defined above.
The present invention comprises the aforesaid compound as therapeutic active substance equally, in particular as treating and/or preventing the treatment of diseases active substance of regulating by thyroid hormone analogs, metabolic trouble particularly, as obesity, hyperlipidaemia, hypercholesterolemia and diabetes, and NASH (NA fatty liver), atherosclerosis, cardiovascular disorder, hypothyroidism, thyroid carcinoma and associated conditions and disease.
In another embodiment preferred, the present invention relates to the method for a kind for the treatment of and/or preventing property treatment by the disease of thyroid hormone analogs adjusting, metabolic trouble particularly, as obesity, hyperlipidaemia, hypercholesterolemia and diabetes, and NASH (NA fatty liver), atherosclerosis, cardiovascular disorder, hypothyroidism, thyroid carcinoma and associated conditions and disease, this method comprises compound as defined above to human or animal's administration.The amount of the compound of preferred administration for about 0.01mg/kg to about 50mg/kg every day, the extremely about 10mg/kg of 0.3mg/kg every day more preferably from about, the also extremely about 3.5mg/kg of 0.70mg/kg every day more preferably from about.
The present invention also comprises application of compound as defined above, the disease that it is used for the treatment of and/or prophylactic treatment is regulated by thyroid hormone analogs, metabolic trouble particularly, as obesity, hyperlipidaemia, hypercholesterolemia and diabetes, and NASH (NA fatty liver), atherosclerosis, cardiovascular disorder, hypothyroidism, thyroid carcinoma and associated conditions and disease.
The invention still further relates to aforesaid application of compound, it is used to prepare medicine, the disease that described medicine is used for the treatment of and/or prophylactic treatment is regulated by thyroid hormone analogs, metabolic trouble particularly, as obesity, hyperlipidaemia, hypercholesterolemia and diabetes, and NASH (NA fatty liver), atherosclerosis, cardiovascular disorder, hypothyroidism, thyroid carcinoma and associated conditions and disease.This medicine comprises aforesaid compound.
Preventing and/or treating of metabolic trouble is preferred indication.More preferably diabetes, particularly non insulin dependent diabetes (2 type).Obesity also is preferred.Hyperlipidaemia also is preferred, particularly hypercholesterolemia.
Compound of the present invention can be begun and adopted the preparation of common synthetic technology well known by persons skilled in the art and program by commercially available raw material.Chromatogram supply and equipment can be available from such companies, AnaLogix for example, Inc, Burlinton, Wisconsin; Analytical Sales and Services, Inc.Pompton Plains, New Jersey; Teledyne Isco, Lincoln, New England; VWRInternational, Bridgeport, New Jersey; With Rainin Instrument Company, Wo Ben, Massachusetts.Chemical can be available from following company, for example Aldrich, ArgonautTechnologies, VWR and Lancaster.What outline below is the reaction scheme that is fit to the such compound of preparation.Further example is the specific embodiment of face detailed description as follows.
Scheme 2
Compound 10a and 10b are according to the series reaction synthetic in outlining among the scheme 1-3.The raw material that is used for synthetic 10a is a 4-hydroxyl-2,6-dimethyl phenyl acetic acid methyl esters, 6a, it is to adopt Gardner, P.D. etc., in JACS (J.Amer.Chem.Soc.), 1959,81, the program of describing in 3364, as shown in scheme 1, from commercially available 2, the 6-xylenol is through 5 step synthetic.3, the 6-dichloro-pyridazine, through alkylation obtain compound 7 (scheme 2) (referring to for example, the organic preparation and the program world (OrganicPreparations and Procedures International), 1988,20 (1-2), 117-121).Use the organo-metallic halogenide of alkali and catalytic amount, in the temperature that raises with compound 6a and compound 7 condensations to obtain 8a (referring to for example, Yuhpyng L.C. etc., PCT international application (1996) WO 9639388).Via the program of routine, the basic hydrolysis of carrying out the methyl esters of 8a obtains compound 9a.Under acidic conditions, carry out chlorine pyridazine 9a to the conversion of pyridazinone (pyridizinone) 10a (referring to for example, chemistry meeting will PerkinTrans.1: organic and bioorganic chemistry (J.Chem.Soc.Perkin Trans.1:Org.andBioorg.Chem.), 1988,12,3103-3111).Begin synthetic compound 10b in the mode identical from compound 6b with 10a.To begin synthetic compound 6b from compound 1b with the similar mode of 6a (scheme 1).
Compound 14 is synthetic according to the series reaction that outlines in scheme 4.Synthetic 14 raw material is 2-(4-hydroxy phenyl) ethanol, its under the bromination condition of routine, be converted to 11 (referring to for example, JACS (J.Amer.Chem.Soc.), 1989,111 (24), 8912-8914).In N,N-dimethylacetamide, at high temperature adopt potassium tert.-butoxide to finish the condensation of compound 7 and compound 11, preparation compound 12.Adopt Anelli, P.L. etc., at organic chemistry magazine (J.Org.Chem.), 1987,52 (12), the similar program described in the 2559-2562, oxygenated compound 12 is with preparation compound 13.Under foregoing condition, chlorine pyridazine 13 changed into pyridazinone (pyridizinone) 14.
Scheme 5
According to the series reaction synthetic compound 19 that in scheme 5, outlines.Synthetic 19 raw material is a 4-hydroxyphenyl acetic acid methyl esters, its under the chlorization condition of routine, be converted to compound 15 (referring to for example, Maeda, R. etc., chemical pharmacy communique (Chem.Pharm.Bull.), 1983,31 (10), 3424-3445).Use lithium aluminum hydride, in tetrahydrofuran (THF),, compound 15 is reverted to compound 16 in low temperature and short reaction times.Formerly under the condition of Miao Shuing compound 16 is changed into pyridazinone 19 through 3 steps.
According to the series reaction synthetic compound 23 that in scheme 6, outlines.Formerly carry out 2-(4-hydroxy phenyl) alcoholic acid bromination under the condition of Miao Shuing with preparation compound 20.In N,N-dimethylacetamide, at high temperature, use potassium tert.-butoxide, preparation compound 21 with compound 20 and compound 7 condensations.By Jones oxidation with compound 21 be oxidized to compound 22 (referring to for example, Bowden, K. etc., chemistry can will (J.Chem.Soc.), 1946,39-45).Under the condition of formerly describing chlorine pyridazine analogue 22 is changed into pyridazinone 23 then.In a similar fashion 3 of Synthetic 23,5-dichlorophenyl analogue, 23 3,5-3,5-dimethylphenyl analogue, 23 3-chloro-5-aminomethyl phenyl analogue, 23 3-bromo-5-aminomethyl phenyl analogue and 23 3-bromo-5-chloro-phenyl-analogue.
According to the series reaction synthetic compound 26 that in scheme 7, outlines.By previously described program, with raw material, 4-amino-2, the 6-chlorophenesic acid, with compound 7 condensations with the preparation compound 24.By previously described program chlorine pyridazine 24 is changed into pyridazinone.Under the standard aqueous alkaline condition, carry out the hydrolysis of gained ethanamide, preparation compound 25.Use cyano group borohydride (MP-cyano group borohydride, commercially available) and oxoethanoic acid on resin then, compound 25 is changed into compound 26 via reduction amination from Argonaut Technologies.In a similar fashion 3 of Synthetic 26,5-dibromo phenyl analogue, 26 3,5-3,5-dimethylphenyl analogue, 26 3-chloro-5-aminomethyl phenyl analogue, 26 3-bromo-5-aminomethyl phenyl analogue and 26 3-bromo-5-chloro-phenyl-analogue.
According to the series reaction synthetic compound 29 that in scheme 8, outlines.Adopt the methyl oxalyl chloride, via the acidylate of amine, with compound 24 change into compound 27 (referring to for example, Sellstedt.J.H. etc., pharmaceutical chemistry magazine (J.Med.Chem.), 1975,18 (9), 926-933).Adopt standard conditions, by α-ketone ester is hydrolyzed into alpha-ketoacid, with compound 27 change into compound 28 (referring to for example, Minisci, F. etc., organic chemistry magazine (J.Org.Chem.), 1995,60,5430-5433).By previously described program chlorine pyridazine 28 is changed into pyridazinone 29.In a similar fashion 3 of Synthetic 29,5-dibromo phenyl analogue, 29 3,5-3,5-dimethylphenyl analogue, 29 3-chloro-5-aminomethyl phenyl analogue, 29 3-bromo-5-aminomethyl phenyl analogue and 29 3-bromo-5-chloro-phenyl-analogue.
According to the series reaction synthetic compound 31 that in scheme 9, outlines.According to Carroll, R.D. etc., pharmaceutical chemistry magazine (J.Med.Chem.), 1983,26, the program among the 96-100 changes into cyano group acetylamino ethyl formate 30 with compound 25.According to Carroll, R.D. etc., pharmaceutical chemistry magazine (J.Med.Chem.), 1983,26, the program of 96-100, carry out compound 30 urethanum cyclisation with the preparation cyano group-azauracil 31.Can synthesize in a similar fashion 31 3,5-dibromo phenyl analogue, 31 3,5-3,5-dimethylphenyl analogue, 31 3-chloro-5-aminomethyl phenyl analogue, 31 3-bromo-5-aminomethyl phenyl analogue and 31 3-bromo-5-chloro-phenyl-analogue.
Scheme 10
According to the series reaction synthetic compound 33 that in scheme 10, outlines.Via Carroll, R.D. etc., pharmaceutical chemistry magazine (J.Med.Chem.), 1983,26, the program of describing among the 96-100 by cyan-hydrolysis is become carboxylic acid, changes into compound 32 with compound 31.Adopt Carroll then, R.D. etc., pharmaceutical chemistry magazine (J.Med.Chem.), 1983,26, the described program of 96-100 changes into compound 33 by decarboxylation with compound 32.Can synthesize in a similar fashion 33 3,5-dibromo phenyl analogue, 33 3,5-3,5-dimethylphenyl analogue, 33 3-chloro-5-aminomethyl phenyl analogue, 33 3-bromo-5-aminomethyl phenyl analogue and 33 3-bromo-5-chloro-phenyl-analogue.
According to the series reaction synthetic compound 37 that in scheme 11, outlines.By previously described program chlorine pyridazine 17 is changed into pyridazinone 34.According to being similar at pharmaceutical chemistry magazine (J.Med.Chem.), 1989,32 (10), the program described in the 2381-2388, use alkali and methyl-iodide with pyridazinone 34 alkylations with preparation compound 35.Under the alkaline condition of standard, acetic ester 35 is hydrolyzed into alcohol 36 (referring to for example, Hauser, C.R. etc., JACS (J.Amer.Chem.Soc.), 1945,67,409-412).By Jones oxidation compound 36 is oxidized to compound 37 then.Can synthesize in a similar fashion 37 3,5-dibromo phenyl analogue, 37 3,5-3,5-dimethylphenyl analogue, 37 3-chloro-5-aminomethyl phenyl analogue, 37 3-bromo-5-aminomethyl phenyl analogue and 37 3-bromo-5-chloro-phenyl-analogue.
According to the series reaction synthetic compound 42 that in scheme 12, outlines.Adopt previously described condition compound 11 to be changed into compound 42 through 5 steps.Can synthesize in a similar fashion 42 3,5-dichlorophenyl analogue, 42 3,5-3,5-dimethylphenyl analogue, 42 3-chloro-5-aminomethyl phenyl analogue, 42 3-bromo-5-aminomethyl phenyl analogue and 42 3-bromo-5-chloro-phenyl-analogue.
According to the series reaction synthetic compound 48 that in scheme 13, outlines.By using the chlorine of 2 of the anion-selective displacements that form by the cyanoacetic acid tert-butyl ester, with raw material, 1,2,3-three chloro-5-oil of mirbane change into compound 43 (referring to for example, Salturo, F. etc., PCT WO 00/17204).Use standard conditions that the nitroreduction of compound 43 is become amine.Tertiary butyl ester hydrolysis and decarboxylation with 43 obtain compound 44 (referring to for example, Salturo, F. etc., PCT WO 00/17204).Employing is similar to Salturo, F. etc., and PCT WO 00/17204 described program, negatively charged ion and compound 7 condensations with compound 44 obtain compound 45.Under the high-temperature acidic condition, chlorine pyridazine 45 is changed into pyridazinone 46.Under these conditions, cyan-hydrolysis is become carboxylic acid, adopt Carroll then, R.D. etc., pharmaceutical chemistry magazine (J.Med.Chem.), 1983,26, the described program decarboxylation of 96-100.With previously described 2 steps compound 46 is changed into compound 48.Can synthesize in a similar fashion 48 3,5-dibromo phenyl analogue, 48 3,5-3,5-dimethylphenyl analogue, 48 3-chloro-5-aminomethyl phenyl analogue, 48 3-bromo-5-aminomethyl phenyl analogue and 48 3-bromo-5-chloro-phenyl-analogue.
According to the series reaction synthetic compound 50 that in scheme 14, outlines.Obtain compound 50 with previously described 2 steps by compound 48.Can synthesize in a similar fashion 50 3,5-dibromo phenyl analogue, 50 3,5-3,5-dimethylphenyl analogue, 50 3-chloro-5-aminomethyl phenyl analogue, 50 3-bromo-5-aminomethyl phenyl analogue and 50 3-bromo-5-chloro-phenyl-analogue.
According to the series reaction synthetic compound 56 that in scheme 15, outlines.Adopt standard conditions with the amine of compound 46 change into compound 51 bromide (referring to for example, Doyle, M.P. etc., organic chemistry magazine (J.Org.Chem.), 1977,42 (14), 2426-2431).By the catalytic carbonylation of the palladium in methyl alcohol, with bromide 51 change into methyl esters 52 (referring to for example, Takatori, K. etc., tetrahedron (Tetrahedron), 1998,54,15861-15869).Employing standard reductive condition is handled with diisobutylaluminium hydride in tetrahydrofuran (THF), with compound 52 be reduced into compound 53 (referring to for example, Yoon, N.M. etc., organic chemistry magazine (J.Org.Chem.), 1985,50,2443-2450).Adopt standard conditions with alcohol 53 change into bromide 54 (referring to for example, Lan, Aj.J.Y. etc., JACS (J.Amer.Chem.Soc.), 1987,109,2738-2745).Adopt Law, H. etc., pharmaceutical chemistry magazine (J.Med.Chem.), 1998,41, the described program of 2243-2251 replaces bromide 54 usefulness sodium cyanides with preparation nitrile 55.Program by routine is hydrolyzed into carboxylic acid with nitrile under the aqueous acidic condition, with nitrile 55 be hydrolyzed into acid 56 (referring to for example, Wenner, O. organic synthesis (Org.Synth.); Total volume IV, 1963,760).In a similar fashion, can synthesize 56 3,5-3,5-dimethylphenyl analogue, 56 3-chloro-5-aminomethyl phenyl analogue, 56 3-bromo-5-aminomethyl phenyl analogue and 56 3-bromo-5-chloro-phenyl-analogue.
Scheme 16
According to the series reaction synthetic compound 64 that in scheme 16, outlines.Under standard bromination condition with raw material, 3,5-two bromo-methyl 4 methylbenzoate brominations with preparation compound 57 (referring to for example, Buu-Hoy, P. etc., organic chemistry magazine (J.Org.Chem.), 1953,18,649-652).With previously described 2 steps compound 57 is changed into compound 59.Program by routine changes into THP trtrahydropyranyl ether with alcohol, with alcohol 59 change into ether 60 (referring to for example, Miyashita, M. etc., organic chemistry magazine (J.Org.Chem.), 1977,42,3882-3774).Adopt and Salturo, F. etc., the described similar program of PCT WO00/17204 at high temperature, at N, in the dinethylformamide, uses sodium hydride to finish the condensation of compound 7 and compound 60 with preparation compound 61.Under acidic conditions, handle compound 61 at elevated temperatures.These reaction conditionss cause the conversion of chlorine pyridazine to pyridazinone (pyridzinone), and the nitrile partial hydrolysis becomes carboxylic acid, then are the decarboxylations of acid, and the alcohol of THP trtrahydropyranyl protection is to the conversion of the benzyl chloride of compound 62.Adopt and Law, H. etc., pharmaceutical chemistry magazine (J.Med.Chem.), 1998,41, the similar program of 2243-2251, with the muriate of sodium cyanide displacement compound 62, preparation nitrile 63.According to previously described program by compound 63 synthetic compounds 64.
According to the series reaction synthetic compound 69 that in scheme 17, outlines.At elevated temperatures, in N,N-dimethylacetamide, use potassium tert.-butoxide, with raw material, 4-amino-2,6-two chloro-phenol and compound 7 condensations.Handle the intermediate of gained with Tetra hydro Phthalic anhydride to form phthalic imidine in the temperature that raises then.The phthalic imidine that obtains is heated in containing the Glacial acetic acid of sodium acetate with preparation compound 65.With Sotelo, E. etc., synthesising communication (Synth.Commun.), 2002,32 (11), under the similar condition of those that find among the 1675-1680, the pyridazinone nitrogen of compound 65 is methylated to form compound 66.In the temperature that raises, the phthalic imidine protecting group of using butylamine to remove compound 66 in methyl alcohol obtains compound 67.Adopt previous described method that compound 67 is changed into compound 68 then.In the temperature that raises, in N,N-dimethylacetamide, use potassium acetate that compound 68 is changed into compound 69.In a similar fashion, can synthesize 69 3,5-dibromo phenyl analogue, 69 3,5-3,5-dimethylphenyl analogue, 69 3-chloro-5-aminomethyl phenyl analogue, 69 3-bromo-5-aminomethyl phenyl analogue and 69 3-bromo-5-chloro-phenyl-analogue.
According to the series reaction synthetic compound 76 that in scheme 18, outlines.According to as Chaudhary, S.K. etc., tetrahedron communication (Tet.Lett.), 1979,20 (2), the standard program described in the 99-102, with t-butyldiphenylsilyl ether protection alcohol 16 with preparation compound 70.Adopt D.M.Springer etc., bioorganic pesticide thing chemistry (Bioorg Med.Chem.), 2003,11, the described three step programs of 265-279 change into thiophene 73 with phenol 70.At high temperature, in methyl-sulphoxide, adopt salt of wormwood to finish the condensation of compound 7 and compound 73, preparation compound 74.With previously described two steps compound 74 is changed into pyridazine ketone acid 76.In a similar fashion, can synthesize 76 3,5-dibromo phenyl analogue, 76 3,5-3,5-dimethylphenyl analogue, 76 3-chloro-5-aminomethyl phenyl analogue, 76 3-bromo-5-aminomethyl phenyl analogue and 76 3-bromo-5-chloro-phenyl-analogue.
Scheme 19
By the series reaction that outlines in the scheme 19, synthetic compound 77 and 78.Use formic acid and hydrogen peroxide oxidation thioether 76 with the mixture that forms separable sulfoxide 77 and sulfone 78 (referring to for example, Cragoe, E. J. etc., US4582842, April 15,1986).In a similar fashion, can synthesize 77 and 78 3,5-dibromo phenyl analogue, 77 and 78 3,5-3,5-dimethylphenyl analogue, 77 and 78 3-chloro-5-aminomethyl phenyl analogue, 77 and 78 3-bromo-5-aminomethyl phenyl analogue, and 77 and 78 3-bromo-5-chloro-phenyl-analogue.
Scheme 20
According to the series reaction synthetic compound 88 that in scheme 20, outlines.Formerly under the condition of Miao Shuing with raw material, 2,6 ,-two chloro-4-nitrophenolss change into compound 79.Formerly under the condition of Miao Shuing compound 79 is changed into compound 80.Adopt the standard reaction condition, the iron powder in acidic medium becomes amine 81 (referring to for example, Org.Syn.Coll.Vol.2,1943,471) with the nitroreduction of compound 80.Under the condition of formerly describing compound 81 is changed into compound 88 then.In a similar fashion, can synthesize 88 3,5-dibromo phenyl analogue, 88 3,5-3,5-dimethylphenyl analogue, 88 3-chloro-5-aminomethyl phenyl analogue, 88 3-bromo-5-aminomethyl phenyl analogue and 88 3-bromo-5-chloro-phenyl-analogue.
Scheme 21
According to the series reaction synthetic compound 91 that in scheme 21, outlines.Formerly under the condition of Miao Shuing compound 87 is changed into compound 91.In a similar fashion, can synthesize 91 3,5-dibromo phenyl analogue, 91 3,5-3,5-dimethylphenyl analogue, 91 3-chloro-5-aminomethyl phenyl analogue, 91 3-bromo-5-aminomethyl phenyl analogue and 91 3-bromo-5-chloro-phenyl-analogue.
According to the series reaction synthetic compound 96 that in scheme 22, outlines.In the temperature that raises, under acidic conditions, handle amine 46 with Tetra hydro Phthalic anhydride, form phthalic imidine 92 (referring to for example, Vera, L.M.S. etc., Farmaco, 2003,58 (12), 1283-1288).At Sotelo, E. etc., synthesising communication (Synth.Commun.), 2002,32 (11), the pyridazinone nitrogen with compound 92 under the condition that 1675-1680 outlines methylates.In the temperature that raises, the phthalic imidine protecting group of removing compound 93 under acidic conditions obtains compound 94.Formerly under the condition of Miao Shuing compound 94 is changed into compound 96.In a similar fashion, can synthesize 96 3,5-dibromo phenyl analogue, 96 3,5-3,5-dimethylphenyl analogue, 96 3-chloro-5-aminomethyl phenyl analogue, 96 3-bromo-5-aminomethyl phenyl analogue and 96 3-bromo-5-chloro-phenyl-analogue.
Synthesizing of suggestion
Can adopt standard conditions with alcohol 17 change into bromide 97 (referring to for example, Lan, Aj.J.Y. etc., JACS (J.Amer.Chem.Soc.), 1987,109,2738-2745).Can adopt to be similar to Law, H. etc., pharmaceutical chemistry magazine (J.Med.Chem.), 1998,41, the program of 2243-2251, the bromide of replacing compound 97 with sodium cyanide is with preparation nitrile 98.Adopt known program, for example the temperature that raises with ammonium chloride and sodiumazide handle 98 (referring to for example, synthetic (Synthesis), 1998,6,910-914), nitrile can be changed into tetrazolium as 98 as 98.Under acidic conditions, can finish chlorine pyridazine 99 to the conversion of pyridazinone 100 (referring to for example, chemistry meeting will Perkin Trans.1: organic and bioorganic chemistry (J.Chem.Soc.Perkin Trans.1:Org.and Bioorg.Chem.), 1988,12,3103-3111).In a similar fashion, can synthesize 100 3,5-dibromo phenyl analogue, 100 3,5-3,5-dimethylphenyl analogue, 100 3-chloro-5-aminomethyl phenyl analogue, 100 3-bromo-5-aminomethyl phenyl analogue and 100 3-bromo-5-chloro-phenyl-analogue.
Adopt reductive agent such as lithium aluminum hydride at low temperatures, can be with 3, the reduction of the ester of 5-two chloro-4-methyl hydroxybenzoates, obtain alcohol 101 (referring to for example, organic chemistry magazine (J.Org.Chem.), 1998,63,5658-5661).Can use alkali with compound 101 and compound 7 condensations in the temperature that raises then, obtain 102 (referring to for example, Yuhpyng L.C. etc., PCT international application (1996) WO 9639388).Can adopt previously described condition that alcohol 102 is changed into compound 106.In a similar fashion, can synthesize 106 3,5-dibromo phenyl analogue, 106 3,5-3,5-dimethylphenyl analogue, 106 3-chloro-5-aminomethyl phenyl analogue, 106 3-bromo-5-aminomethyl phenyl analogue and 106 3-bromo-5-chloro-phenyl-analogue.
Adopt Canadian Journal of Chemistry (Can.J.Chem.) 2001,79 (5-6), the condition described in the 752-759 can change into ester 107 with bromide 54.Adopt known procedure, ester can be changed into alcohol as 108 as 107, for example in tetrahydrofuran (THF) with hydrogenation diisobutyl ammonium handle 107 (referring to for example, Yoon, N.M. etc., organic chemistry magazine (J.Org.Chem.), 1985,50,2443-2450).Finish alcohol 108 conversions under the condition that can formerly describe to tetrazolium 111.In a similar fashion, can synthesize 111 3,5-dibromo phenyl analogue, 111 3,5-3,5-dimethylphenyl analogue, 111 3-chloro-5-aminomethyl phenyl analogue, 111 3-bromo-5-aminomethyl phenyl analogue and 111 3-bromo-5-chloro-phenyl-analogue.
Adopt previously described condition, can finish the conversion of nitrile 55 to tetrazolium 112.In a similar fashion, can synthesize 112 3,5-dibromo phenyl analogue, 112 3,5-3,5-dimethylphenyl analogue, 112 3-chloro-5-aminomethyl phenyl analogue, 112 3-bromo-5-aminomethyl phenyl analogue and 112 3-bromo-5-chloro-phenyl-analogue.
Adopt previously described condition, can finish the conversion of compound 74 to compound 116.In a similar fashion, can synthesize 116 3,5-dibromo phenyl analogue, 116 3,5-3,5-dimethylphenyl analogue, 116 3-chloro-5-aminomethyl phenyl analogue, 116 3-bromo-5-aminomethyl phenyl analogue and 116 3-bromo-5-chloro-phenyl-analogue.
Adopt previously described condition, can finish the conversion of compound 116 to compound 117 and 118.In a similar fashion, can synthesize 117 and 118 3,5-dibromo phenyl analogue, 117 and 118 3,5-3,5-dimethylphenyl analogue, 117 and 118 3-chloro-5-aminomethyl phenyl analogue, 117 and 118 3-bromo-5-aminomethyl phenyl analogue, and 117 and 118 3-bromo-5-chloro-phenyl-analogue.
Adopt previously described condition can finish the conversion of compound 101 to compound 127.In a similar fashion, can synthesize 127 3,5-dibromo phenyl analogue, 127 3,5-3,5-dimethylphenyl analogue, 127 3-chloro-5-aminomethyl phenyl analogue, 127 3-bromo-5-aminomethyl phenyl analogue and 127 3-bromo-5-chloro-phenyl-analogue.
Adopt previously described condition can finish the conversion of compound 127 to compound 128 and 129.In a similar fashion, can synthesize 128 and 129 3,5-dibromo phenyl analogue, 128 and 129 3,5-3,5-dimethylphenyl analogue, 128 and 129 3-chloro-5-aminomethyl phenyl analogue, 128 and 129 3-bromo-5-aminomethyl phenyl analogue, and 128 and 129 3-bromo-5-chloro-phenyl-analogue.
Employing is similar to J.Het.Chem.1994, and 31 (6), the program of 1439-43, in the temperature that raises bromo-methyl acetate and alkali-treated raw materials, 2,6-two chloro-benzene-1,4-glycol, preparation compound 130.Adopt previously described condition can finish the conversion of compound 130 to compound 131.Can adopt the aqueous alkaline condition of standard to finish the hydrolysis of ester 131 to compound 132.Adopt previously described condition can finish the conversion of compound 132 to compound 133.In a similar fashion, can synthesize 133 3,5-dibromo phenyl analogue, 133 3,5-3,5-dimethylphenyl analogue, 133 3-chloro-5-aminomethyl phenyl analogue, 133 3-bromo-5-aminomethyl phenyl analogue and 133 3-bromo-5-chloro-phenyl-analogue.
Be similar to Gattermann, L. (1914), Die Praxis des organischen Chemikers (12) under the 228 described conditions, can change into compound 134 with compound 46.Adopt previously described condition can finish the conversion of compound 134 to compound 136.In a similar fashion, can synthesize 136 3,5-dibromo phenyl analogue, 136 3,5-3,5-dimethylphenyl analogue, 136 3-chloro-5-aminomethyl phenyl analogue, 136 3-bromo-5-aminomethyl phenyl analogue and 136 3-bromo-5-chloro-phenyl-analogue.
Adopt previously described condition can finish the conversion of compound 130 to compound 141.In a similar fashion, can synthesize 114 3,5-dibromo phenyl analogue, 141 3,5-3,5-dimethylphenyl analogue, 141 3-chloro-5-aminomethyl phenyl analogue, 141 3-bromo-5-aminomethyl phenyl analogue and 141 3-bromo-5-chloro-phenyl-analogue.
Adopt previously described condition can finish the conversion of compound 141 to compound 142 and 143.In a similar fashion, can synthesize 142 and 143 3,5-dibromo phenyl analogue, 142 and 143 3,5-3,5-dimethylphenyl analogue, 142 and 143 3-chloro-5-aminomethyl phenyl analogue, 142 and 143 3-bromo-5-aminomethyl phenyl analogue, and 142 and 143 3-bromo-5-chloro-phenyl-analogue.
Adopt previously described condition can finish the conversion of compound 94 to compound 149.In a similar fashion, can synthesize 149 3,5-dibromo phenyl analogue, 149 3,5-3,5-dimethylphenyl analogue, 149 3-chloro-5-aminomethyl phenyl analogue, 149 3-bromo-5-aminomethyl phenyl analogue and 149 3-bromo-5-chloro-phenyl-analogue.
Adopt previously described condition can finish the conversion of compound 85 to compound 154.In a similar fashion, can synthesize 154 3,5-dibromo phenyl analogue, 154 3,5-3,5-dimethylphenyl analogue, 154 3-chloro-5-aminomethyl phenyl analogue, 154 3-bromo-5-aminomethyl phenyl analogue and 154 3-bromo-5-chloro-phenyl-analogue.
Adopt previously described condition can finish the conversion of compound 154 to compound 155 and 156.In a similar fashion, can synthesize 155 and 156 3,5-dibromo phenyl analogue, 155 and 156 3,5-3,5-dimethylphenyl analogue, 155 and 156 3-chloro-5-aminomethyl phenyl analogue, 155 and 156 3-bromo-5-aminomethyl phenyl analogue, and 155 and 156 3-bromo-5-chloro-phenyl-analogue.
Adopt previously described condition can finish the conversion of compound 152 to compound 162.In a similar fashion, can synthesize 162 3,5-dibromo phenyl analogue, 162 3,5-3,5-dimethylphenyl analogue, 162 3-chloro-5-aminomethyl phenyl analogue, 162 3-bromo-5-aminomethyl phenyl analogue and 162 3-bromo-5-chloro-phenyl-analogue.
Adopt previously described condition can finish the conversion of compound 162 to compound 163 and 164.In a similar fashion, can synthesize 163 and 164 3,5-dibromo phenyl analogue, 163 and 164 3,5-3,5-dimethylphenyl analogue, 163 and 164 3-chloro-5-aminomethyl phenyl analogue, 163 and 164 3-bromo-5-aminomethyl phenyl analogue, and 163 and 164 3-bromo-5-chloro-phenyl-analogue.
In the enforcement of method of the present invention, with any The compounds of this invention of significant quantity or combination or its medicinal salt or ester of any The compounds of this invention, via in any common and acceptable method known in the art any, separately or administration in combination.Therefore, can be with compound or composition administration in the following manner: per os (for example, oral cavity), the hypogloeeis, parenteral (for example, muscle, vein or subcutaneous), rectum is (for example, adopt suppository or lotion), transdermal (for example, skin electroporation) or suction (for example, adopting aerosol), and adopt the form of solid, liquid or gas formulation, comprise tablet and suspension agent.Administration can adopt continuous treatment to carry out with single unit dosage form, perhaps arbitrarily with single-dose treatment.Therapeutic composition also can be and lipotropy salt such as pamoic acid bonded oil emulsion or dispersion form perhaps to be used for the biodegradable slow releasing composition form of subcutaneous or muscle administration.
The useful pharmaceutical carrier for preparing its composition can be solid, liquid or gas; Therefore, the form of composition can be tablet, pill, capsule, suppository, powder, preparation casing or other protection (for example be combined on the ion exchange resin or be packaged in the lipoprotein vesicle), sustained release preparation, solution, suspension, elixir, aerosol etc.Carrier can be selected from various oils, comprises oil, animal oil, vegetables oil or synthetic oil, for example, and peanut oil, soya-bean oil, mineral oil, sesame wet goods.Water, salt solution, aqueous glucose and dibasic alcohol are preferred liquid vehicles, and particularly (when oozing with blood etc.) is used for injection liquid.For example, the preparation of intravenous administration comprises the aseptic aqueous solution of one or more activeconstituentss, and it is by one or more solid active agents being dissolved in the water with the preparation aqueous solution, and makes this solution aseptic and preparation.Suitable drug excipient comprises starch, Mierocrystalline cellulose, talcum, glucose, lactose, talcum, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silica, Magnesium Stearate, sodium stearate, monostearin, sodium-chlor, skim-milk, glycerine, propylene glycol, water, ethanol etc.Composition can add conventional medicated premix, as sanitas, and the salt of stablizer, moistening or emulsifying agent, change osmotic pressure, buffer reagent etc.Suitable pharmaceutical carrier and their preparation are described in " pharmaceutical science of Lei Mingdun (Remington ' s Pharmaceutical Sciences) " of E.W.Martin.Under any circumstance, these compositions will contain the active compound and the suitable carriers of significant quantity, be used for carrying out suitable administration to the recipient to prepare suitable formulation.
Pharmaceutical preparation can also contain sanitas, solubilizing agent, stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, seasonings, salt, buffer reagent, Drug coating or the antioxidant of change osmotic pressure.They also can contain valuable material in other the treatment, comprise except the other activeconstituents those of formula I.
Compound useful as drug of the present invention, described medicine is used for the treatment of metabolic trouble as obesity, hyperlipidaemia, hypercholesterolemia and diabetes, and can be used for other disease such as NASH, atherosclerosis, cardiovascular disorder, hypothyroidism, thyroid carcinoma and associated conditions and disease.The obese patient is that weight index is the people more than 25.
Can in grace period, change and can measure according to the treatment significant quantity of compound of the present invention or dosage with manner known in the art.This dosage will be adjusted at individual need in each concrete situation, comprise the particular compound of using, route of administration, treatment illness, and the patient who is treated.Usually, at oral or administered parenterally in the situation of the adult patient of heavily about 70Kg, about 0.01mg/kg to the per daily dose of about 50mg/kgg should be suitable, although when there are indications, can surpass the upper limit.Dosage is preferably the extremely about 10mg/kg of about 0.3mg/kg every day.Preferred dosage can for about 0.70mg/kg to about 3.5mg/kg every day.Per daily dose can be used as single dose or divided dose is used, and perhaps for administered parenterally, it can be used as continuous infusion and gives.
Formula (I) compound is a thyroid hormone analogs.Shown in the following embodiments, adopt TR/RXR/GRIP to test test formula (I) compound.Therefore, the compound of test is a thyroid hormone receptor agonists, and its EC50 is below the 1000 μ M, and preferred EC50 is below the 100 μ M.
Present invention will be further described in the following example, and these embodiment illustrate for example rather than limit the scope of the invention.
Embodiment
Scheme 1: synthetic 4-hydroxyl-2,6-dimethyl phenyl acetic acid methyl esters (6a) and 2-chloro-4-hydroxyl-6-aminomethyl phenyl methyl acetate (6b)
Scheme 2: synthesize 3,6-two chloro-4-sec.-propyl pyridazines (7)
Scheme 3: synthetic [4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-3,5-dimethyl-phenyl]-acetate (10a) and synthetic [3-chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-5-methyl-phenyl]-acetate (10b)
Embodiment 1: synthetic [4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-3,5-dimethyl-phenyl]-acetate (10a)
Step 1: preparation 4-dimethylaminomethyl-2,6-dimethyl-phenol (2a)
With 2 under the room temperature, the 6-xylenol (20g, 0.163mol) (solution in ethanol (100mL) 0.163mol) is handled, and then (37% formalin of 13.5mL 0.163mol) is handled with formaldehyde with dimethylamine by 40% dimethylamine agueous solution of 19mL.Reaction is heated to backflow 12h.Reaction mixture is cooled to 0 ℃ in ice bath, water (100mL) dilutes and is adjusted to pH=5 with the 1N aqueous hydrochloric acid.(2 * 150mL) extract water layer with ether.Water layer is adjusted to pH=8 by adding the 1N aqueous sodium hydroxide solution, in ice bath, be cooled to 0 ℃ and with ether (3 * 200mL) extract.Organism is washed with saturated sodium-chloride water solution, and dried over mgso is filtered and vacuum concentration.The oily matter that obtains is dried overnight under high vacuum, obtains 4-dimethylaminomethyl-2, and 6-dimethyl-phenol is pale solid (13.42g, 46%); EI (+)-HRMS m/z:C
11H
17NO (M
+) calculated value 179.1310, the actual measurement 179.1308.Molecular weight=179.2642; Exact mass=179.1310
Step 2: preparation 2,6-dimethyl-4-trimethylammonium amino methyl phenol (3a)
(2.08mL 0.033mol) handles 4-dimethylaminomethyl-2,6-dimethyl-phenol (2a) (3.0g, 0.016mol) suspension in ether (25mL) with methyl-iodide in room temperature.In reaction, add other ether (20mL).With reaction mixture in stirred overnight at room temperature.Wash with the solid filtering that obtains and with ether.There are raw material in NMR and LCMS demonstration.Solid is dropped into reaction conditions again.To be reflected at stirring at room 2d.At this moment, add other methyl-iodide (2.08mL, 0.033mol).To be reflected at stirred overnight at room temperature.At this moment, wash with the solid filtering that obtains and with ether.Solid is dry under high vacuum, obtain 2,6-dimethyl-4-trimethylammonium amino methyl phenol (3a) (5.1g, crude product) is white solid, with it without use with being further purified.Molecular weight=195.3073; Exact mass=195.1623
Step 3: preparation (3,5-dimethyl-4-hydroxyl-phenyl)-acetonitrile (4a)
With 2 under the argon gas, 6-dimethyl-4-trimethylammonium amino methyl phenol (3a) (in theory, 0.016mol) solution in ethanol (50mL) (976mg 0.019mol) handles with sodium cyanide in room temperature.Reaction mixture is heated to backflow to spend the night.Then with reaction mixture dilute with water and acidifying by adding the 1N aqueous hydrochloric acid.(3 * 200mL) extract with ethyl acetate with mixture.With the organism water that merges (1 * 200mL) and saturated sodium-chloride water solution (filtration and vacuum concentration obtain brown solid for 1 * 200mL) washing, dried over mgso.Solid is formed slurries and passes through to filter collection in ether (50mL).Solid by using the column chromatography purifying of silica gel, is used in the 10-15% eluent ethyl acetate in the sherwood oil, obtains 3,5-dimethyl-4-hydroxyl-phenyl)-acetonitrile (4a), be yellow solid (1.61g, two step productive rates are 60%); EI (+)-HRMS m/z:C
10H
11NO (M
+) calculated value 161.0841, actual measurement 161.0841.Molecular weight=161.2053; Exact mass=161.0841
Step 4: preparation (3,5-dimethyl-4-hydroxyl-phenyl)-acetate (5a)
(550mg, 0.003mol) (6.6mL 0.063mol) handles the suspension spent glycol dme in water (0.98mL), and then (1.34g 0.024mol) handles with potassium hydroxide with (3,5-dimethyl-4-hydroxyl-phenyl)-acetonitrile (4a).Reaction mixture is heated to backflow 2d.With the reaction mixture vacuum concentration.(2 * 75mL) extract with the dilution of the solid water (100mL) that obtains and with ethyl acetate.Abandon organic layer.With water layer by adding the 1N aqueous hydrochloric acid and be acidified to pH=2 and (2 * 100mL) extracting with ethyl acetate.Organic layer is merged, and (2 * 50mL) washings, dried over mgso is filtered and vacuum concentration with saturated sodium-chloride water solution.Solid by using the column chromatography purifying of silica gel, is used in the 15-25% eluent ethyl acetate in the sherwood oil, obtains (3,5-dimethyl-4-hydroxyl-phenyl)-acetate (5a) (30mg, 5%), be yellow solid; EI (+)-HRMS m/z:C
10H
12O
3(M
+) calculated value 180.0786, actual measurement 180.0782.Molecular weight=180.2053; Exact mass=180.0786
Step 5: preparation (3,5-dimethyl-4-hydroxyl-phenyl)-methyl acetate (6a)
(12.4g, 0.069mmol) solution in methyl alcohol (300mL) is handled with the vitriol oil (6.25mL) with (3,5-dimethyl-4-hydroxyl-phenyl)-acetate (5a).The solution that obtains is heated to 70 ℃ to spend the night.At this moment, will react cool to room temperature.To react vacuum concentration.Resistates dilutes with ethyl acetate (700mL) and water (2 * 250mL) washings.The organic layer dried over mgso is filtered and vacuum concentration, obtains orange solids.This solid is formed slurries and stirs 1h in 10% ethyl acetate/petroleum ether.Solid collected by filtration, with the washing of 10% ethyl acetate/petroleum ether, and vacuum-drying is spent the night.Resistates by using the column chromatography purifying of silica gel, is used in the 10-15% eluent ethyl acetate in the sherwood oil, obtains (3,5-dimethyl-4-hydroxyl-phenyl)-methyl acetate (6a) (1.93g, 86%), be pale solid; EI (+)-HRMS m/z:C
11H
14O
3(M
+) calculated value 194.0943, actual measurement 191.0942.Molecular weight=194.2324; Exact mass=194.0943
Step 6: preparation 3,6-two chloro-4-sec.-propyl pyridazines (7)
With 3 under the room temperature, (22.5g, 0.15mol) (14mL 0.151mol) handles the 6-dichloro-pyridazine, and then (13g 0.075mol) handles with Silver Nitrate with isopropylformic acid at the solution of acetonitrile (35mL), tetramethylene sulfone (107mL) and water (245mL).Reaction mixture is heated to 55 ℃.The solution of the disposable adding vitriol oil (24mL) in water (75mL) then drips ammonium persulphate (51.5g, 0.22mol) solution in water (75mL) in 35min.Reaction mixture is heated to 70 ℃, lasts 20min, then cool to room temperature and stirring 24h.At this moment, reaction is cooled to 0 ℃, and slowly drips 28-30% ammonium hydroxide (100mL) so that reaction reaches pH=8.To react water (500mL) dilution, on C salt, filter and with ethyl acetate (500mL) thorough washing.Separate water layer and organic layer.Keep organic layer.(2 * 500mL) extract water layer with ethyl acetate.With the organism water that merges (1 * 400mL) and saturated sodium-chloride water solution (1 * 400mL) washing, dried over mgso, filtration and vacuum concentration.The oily matter that obtains by using the column chromatography purifying of silica gel, is used sherwood oil, then is 10% eluent ethyl acetate in sherwood oil, obtains 3, and 6-two chloro-4-sec.-propyl pyridazines (7) (19.26g, 67%) are oily matter; (+)-HRMS m/z:C
7H
8Cl
2N
2(M
+) calculated value 190.0065, actual measurement 190.0059.Molecular weight=191.0612; Exact mass=190.0065
Step 7: preparation [4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-3,5-dimethyl-phenyl]-methyl acetate (8a)
With (3 under room temperature, the argon gas, 5-dimethyl-4-hydroxyl-phenyl)-methyl acetate (6a) (12.5g, 0.064mol) solution in anhydrous dimethyl sulfoxide (256mL) is with 3,6-two chloro-4-sec.-propyl pyridazine (7) (18.43g, 0.096mol) handle, then with Anhydrous potassium carbonate (17.69g, 0.12mol) and cupric iodide (I) (6.09g, 0.032mol) processing.Reaction mixture is heated to 90 ℃, lasts 24h.At this moment, with the reactant cool to room temperature and be poured on 1N aqueous hydrochloric acid (200mL) and on ice.(2 * 500mL) extract with water layer dilute with water (100mL) and with ethyl acetate.By adding the 1N aqueous sodium hydroxide solution, make water layer become alkalescence (pH=8).Water layer is used ethyl acetate (1 * 500mL) extraction once more.The organism that merges is washed with saturated sodium-chloride water solution, and dried over mgso is filtered and vacuum concentration.The resistates that obtains is passed through to use the column chromatography purifying of silica gel, be used in the 5-15% eluent ethyl acetate in the sherwood oil, obtain [4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-3,5-dimethyl-phenyl]-methyl acetate (8a) (15g, 67%) and a spot of isomer, is white solid; EI (+)-HRMS m/z:C
18H
21ClN
2O
3(M
+) calculated value 348.1241, actual measurement 348.1237.Molecular weight=348.8327; Exact mass=348.1241
Step 8: preparation [4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-3,5-dimethyl-phenyl]-acetate (9a)
With [the 4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-3 under the room temperature, 5-dimethyl-phenyl]-methyl acetate (8a) (1.66g, 4.75mmol, containing a spot of isomer) and (9.5mL 9.50mmol) handles by dripping the 1N aqueous sodium hydroxide solution for solution in methyl alcohol (50mL).With reactant at stirring at room 24h.At this moment, with the reaction mixture vacuum concentration.Extract with the dilution of the solid water (200mL) that obtains and with ethyl acetate (200mL).Abandon ethyl acetate layer.Water layer is acidified to pH=4 by adding the 1N aqueous hydrochloric acid, and (2 * 200mL) extract with ethyl acetate.Organic layer is merged, and with the saturated sodium-chloride water solution washing, dried over mgso is filtered and vacuum concentration, obtains solid.With solid dried overnight under high vacuum, obtain [4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-3,5-dimethyl-phenyl]-acetate (9a) (1.58g, 100%, contain a spot of isomer), be pale solid; EI (+)-HRMS m/z:C
17H
19ClN
2O
3(M
+) calculated value 334.1084, actual measurement 334.1083.Molecular weight=334.8056; Exact mass=334.1084
Step 9: preparation [4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-3,5-dimethyl-phenyl]-acetate (10a)
Will [4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-3,5-dimethyl-phenyl]-acetate (9a) (0.10g, the 0.29mol) sodium acetate of the solution in Glacial acetic acid (3mL) (54mg, 0.65mol) processing in room temperature.Reaction mixture is heated to 100 ℃, lasts 24h.At this moment, with reaction mixture cool to room temperature and vacuum concentration.With the residue diluted with water (100mL) that obtains, become alkalescence by adding the 1N aqueous sodium hydroxide solution, and extract with ethyl acetate (200mL).Abandon ethyl acetate layer.With water layer by adding the 1N aqueous hydrochloric acid and be acidified to pH=4 and (2 * 200mL) extracting with ethyl acetate.Organic layer is merged, and with the saturated sodium-chloride water solution washing, dried over mgso is filtered and vacuum concentration, obtains solid.By adding methyl alcohol solid is dissolved in the ethyl acetate to form solution, is adsorbed onto on the silicon-dioxide it and vacuum concentration.By using the column chromatography of silica gel, be used in 20% eluent ethyl acetate in the hexane that contains 2% Glacial acetic acid, with the solid purifying of preadsorption.With required fraction concentrate for several separate batch and place 1h under the high vacuum.Obtain
1Whether H NMR only contains required isomer in definite batch.Best batch is merged, and with 1: 1 methylene dichloride: hexane solution diluted.This process is carried out three times.With solid dried overnight under high vacuum, in acetonitrile, form slurries and filtration then.With the solid that obtains in vacuum oven in 60 ℃ of dry 24h, obtain [4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-3,5-dimethyl-phenyl]-acetate (10a) (61mg, 65%), be white solid; EI (+)-HRMS m/z:C
17H
20N
2O
4(M
+) calculated value 316.1423, actual measurement 316.1427.Molecular weight=316.3599; Exact mass=316.1423
Embodiment 2: preparation [3-chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-5-methyl-phenyl]-acetate (10b)
Step 1: preparation 2-chloro-4-dimethylaminomethyl-6-methyl-phenol (2b)
(5.0g, 0.035mol) (0.035mol) handle, and then (37% formalin of 2.85mL 0.035mol) is handled with formaldehyde by 40% dimethylamine agueous solution of 3.95mL with dimethylamine for the solution in ethanol (25mL) with the 2-chloro-6-methylphenol of room temperature.Reaction is heated to backflow 24h.At this moment, with reaction mixture cool to room temperature and vacuum concentration.Be acidified to pH=2 with the dilution of the oily matter water (200mL) that obtains and by adding the 1N aqueous hydrochloric acid.Water layer is extracted with ethyl acetate (300mL).Abandon ethyl acetate layer.With water layer by adding the 1N aqueous sodium hydroxide solution and be basified to pH=10 and (2 * 350mL) extracting with ethyl acetate.Organism is washed with saturated sodium-chloride water solution, and dried over mgso is filtered and vacuum concentration.With the oily matter dried overnight under high vacuum that obtains, obtain 2-chloro-4-dimethylaminomethyl-6-methyl-phenol (2b) (4.62g, 66%), be pale solid; EI (+)-HRMS m/z:C
10H
14ClNO (M
+) calculated value 199.0764, actual measurement 199.0767.Molecular weight=199.6822; Exact mass=199.0764
Step 2: preparation 2-chloro-6-methyl-4-trimethylammonium amino methyl phenol (3b)
(65.5g, 0.328mol) (40.83mL 0.65mol) handles in room temperature the suspension in ether (1.5L) with methyl-iodide with the 2-chloro-4-dimethylaminomethyl-6-methyl-phenol (2b) under the argon gas.With reaction mixture in stirred overnight at room temperature.Wash with the solid filtering that obtains and with ether this moment.Solid is dry under high vacuum, obtain 2-chloro-6-methyl-4-trimethylammonium amino methyl phenol (3b), be pale solid, its tale quale is used for next step.Molecular weight=215.7252; Exact mass=215.1077
Step 3: preparation (3-chloro-4-hydroxy-5-methyl base-phenyl)-acetonitrile (4b)
(16.01g 0.32mol) handles the 2-chloro-6-methyl-suspension of 4-trimethylammonium amino methyl phenol (3b) (0.32mol in theory) in ethanol (2L) that will be under argon gas with sodium cyanide in room temperature.Reaction mixture is heated to backflow 2d.At this moment, with the reaction mixture vacuum concentration.Be acidified to pH=2 with the residue diluted with water that obtains and by adding the 1N aqueous hydrochloric acid.(3 * 600mL) extract water layer with ethyl acetate.Organic layer is merged, and with the saturated sodium-chloride water solution washing, dried over mgso is filtered and vacuum concentration, obtains brown solid.Solid is dissolved in the tetracol phenixin (250mL), and with remaining black jelly via removing by filter.Be that room temperature leaves standstill the back and form throw out in filtrate.With solid filtering, with the hexane flushing, and dry under high vacuum, obtain (3-chloro-4-hydroxy-5-methyl base-phenyl)-acetonitrile (4b) (30.3g), be yellow solid.Filtrate is concentrated, and the resistates that obtains by using the column chromatography purifying of silica gel, is used in the 5-10% eluent ethyl acetate in the sherwood oil, obtains (3-chloro-4-hydroxy-5-methyl base-phenyl)-acetonitrile (4b) (2.28g, the overall yield in 2 steps is 55%), be yellow solid; EI (+)-HRMS m/z:C
9H
8ClNO (M+) calculated value 181.0294, actual measurement 181.0295. molecular weight=181.6232; Exact mass=181.0294
Step 4: preparation (3-chloro-4-hydroxy-5-methyl base-phenyl)-acetate (5b)
(1.3g, 0.0071mol) (13.93mL 0.133mol) handles the suspension spent glycol dme in water (2.06mL), and then (2.8g 0.0071mol) handles with potassium hydroxide with (3-chloro-4-hydroxy-5-methyl base-phenyl)-acetonitrile (4b).Reaction mixture is heated to backflow 24h.At this moment, with the reaction mixture vacuum concentration.(2 * 50mL) extract with the dilution of the solid water (100mL) that obtains and with ethyl acetate.Abandon organic layer.With water layer by adding the 1N aqueous hydrochloric acid and be acidified to pH=2 and (2 * 50mL) extracting with ethyl acetate.Organic layer is merged, and with saturated sodium-chloride water solution (50mL) washing, dried over mgso is filtered and vacuum concentration.Solid dried overnight under high vacuum with obtaining obtains (3-chloro-4-hydroxy-5-methyl base-phenyl)-acetate (5b) (1.4g, 97%), is white solid; EI (+)-HRMS m/z:C
9H
9ClO
3(M
+) calculated value 200.0240, actual measurement 200.0247.Molecular weight=200.6233; Exact mass=200.0240
Step 5: preparation (3-chloro-4-hydroxy-5-methyl base-phenyl)-methyl acetate (6b)
Under room temperature, argon gas, handle (3-chloro-4-hydroxy-5-methyl base-phenyl)-acetate (5b) (1.4g, 6.98mmol) solution in methyl alcohol (60mL) with the vitriol oil (0.5mL).Reaction mixture is heated to 70 ℃ of 24h.At this moment, with the reaction mixture vacuum concentration.The oily matter that obtains is diluted with ethyl acetate (100mL).(2 * 50mL) washings, dried over mgso are filtered and are concentrated with the organism water.The resistates that obtains by using the column chromatography purifying of silica gel, is used in 10% eluent ethyl acetate in the sherwood oil, obtains 3-chloro-4-hydroxy-5-methyl base-phenyl)-methyl acetate (6b) (1.36g, 91%), be white solid; EI (+)-HRMS m/z:C
10H
11ClO
3(M
+) calculated value 214.0397, actual measurement 214.0400.Molecular weight=214.6504; Exact mass=214.0397
Step 6: preparation [3-chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-5-methyl-phenyl]-methyl acetate (8b)
Will be at the 3-chloro-4-hydroxy-5-methyl base-phenyl under room temperature, the argon gas)-methyl acetate (6b) (909mg, 0.004mol) solution in anhydrous dimethyl sulfoxide (8mL) is with 3,6-two chloro-4-sec.-propyl pyridazine (7) (1.2g, 0.006mol), Anhydrous potassium carbonate (1.15g, 0.008mol) and cupric iodide (I) (239mg, 0.001mol) processing.Reaction mixture is heated to 90 ℃ to spend the night.At this moment, with the reaction mixture cool to room temperature, be poured on the 1N aqueous hydrochloric acid and use ethyl acetate extraction.Organism is washed with saturated sodium-chloride water solution, and dried over mgso is filtered and vacuum concentration.The resistates that obtains is passed through to use the column chromatography purifying of silica gel, be used in 10% eluent ethyl acetate in the sherwood oil, obtain [3-chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-5-methyl-phenyl]-methyl acetate (8b) (1.2g, 78%), be yellow solid; EI (+)-HRMS m/z:C
17H
18Cl
2N
2O
3(M
+) calculated value 369.0767, actual measurement 369.0766.Molecular weight=369.2506; Exact mass=368.0694
Step 7: preparation [3-chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-5-methyl-phenyl]-acetate (9b)
With [3-chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-5-methyl-phenyl]-methyl acetate (8b) (1.1g, 2.97mmol) the 1N aqueous sodium hydroxide solution of the solution in methyl alcohol (30mL) (5.9mL, 5.9mmol) the dropwise processing under the room temperature.To be reflected at stirring at room 4d.At this moment, with the reaction mixture vacuum concentration.With solid water and the ethyl acetate dilution that obtains.Abandon ethyl acetate layer.With water layer by adding 1N aqueous hydrochloric acid acidifying and using ethyl acetate extraction.Organic layer is washed with saturated sodium-chloride water solution, and dried over mgso is filtered and vacuum concentration, obtains [3-chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-5-methyl-phenyl]-acetate (9b) (1.05g, 100%), is white solid.With this material without using with being further purified; EI (+)-HRMS m/z:C
16H
16Cl
2N
2O
3(M
+) calculated value 355.0611, actual measurement 355.0610.Molecular weight=355.2235; Exact mass=354.0538
Step 8: preparation [3-chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-5-methyl-phenyl]-acetate (10b)
Will [3-chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-5-methyl-phenyl]-acetate (9b) (1.0g, the 2.81mmol) sodium acetate of the solution in Glacial acetic acid (30mL) (808mg, 9.83mmol) processing in room temperature.Reaction mixture is heated to 105 ℃, lasts 24h.At this moment, with reaction mixture cool to room temperature and vacuum concentration.With the residue diluted with water that obtains, be adjusted to pH=10 and use ethyl acetate extraction by adding the 1N aqueous sodium hydroxide solution.Abandon ethyl acetate layer.With water layer by adding 3N aqueous hydrochloric acid acidifying and using ethyl acetate extraction.Organic layer is merged, water and saturated sodium-chloride water solution washing, dried over mgso is filtered and vacuum concentration.The solid that obtains is dissolved in methylene dichloride and the methyl alcohol, is adsorbed onto on the silicon-dioxide then.By using the column chromatography of silica gel, be used in 20% eluent ethyl acetate in the hexane that contains 2% Glacial acetic acid, with the solid purifying of preadsorption.With required fraction concentrate for several separate batch and place 15min under the high vacuum.With solid with 1: 1 methylene dichloride: the hexane solution dilution.This process is carried out 3 times.With solid dried overnight under high vacuum.Then solid is formed slurries in acetonitrile, filters, and in vacuum oven in 80 ℃ of dried overnight, obtain [3-chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-5-methyl-phenyl]-acetate (10b) (300mg, 32%), be white solid; EI (+)-HRMS m/z:C
16H
17ClN
2O
4(M+H)
+Calculated value 337.0950, actual measurement 337.0949.Molecular weight=336.7779; Exact mass=336.0877
Scheme 4: synthetic [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (14)
Embodiment 3: synthetic [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (14)
Step 1: preparation 2,6-two bromo-4-(2-hydroxyl-ethyl)-phenol (11)
With 4-(2-hydroxyl-ethyl)-phenol (50g, 0.35mol) bromine (41mL, 0.78mol) solution-treated in Glacial acetic acid (40mL) of the solution in Glacial acetic acid (400mL).With reaction mixture in stirred overnight at room temperature.At this moment, under vacuum, remove and desolvate.With the resistates that obtains with toluene (200mL) dilution and with solvent vacuum concentration once more.The resistates that obtains is dissolved in the tetrahydrofuran (THF) (250mL), and adds 4N aqueous sodium hydroxide solution (350mL), add entry (150mL) subsequently.With reactant at stirring at room 3h.Making reactant by adding concentrated hydrochloric acid (80mL) then is pH=5.Separate each layer (bottom is a product).Water layer extracts with methyl tertiary butyl ether (500mL).Organic layer is merged, dried over sodium sulfate, filtration and vacuum concentration are to about 100mL.Add heptane (100mL) and with the solvent vacuum concentration to about 100mL.With solid filtering and be used in 10% methyl tertiary butyl ether washing in the heptane (150mL).With solid dried overnight under high vacuum, obtain 2,6-two bromo-4-(2-hydroxyl-ethyl)-phenol (11) (86.8g, 82%) are white solid; LRMS:C
8H
8Br
2O
2(M-H) m/z=295.Molecular weight=295.9598; Exact mass=293.8891
Step 2: preparation 2-[3,5-two bromo-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-ethanol (12)
(70.5g 0.59mol) handles 2,6-two bromo-4-(2-hydroxyl-ethyl)-phenol (11) (183.3g, 0.619mol) mixture in N,N-dimethylacetamide (300mL) with potassium tert.-butoxide in room temperature under nitrogen.Suspension is heated to 100 ℃ and stir until forming solution.At this moment, add 3 in solution, (100g 0.50mol), and stirs 24h with reaction mixture at 135 ℃ to 6-two chloro-4-sec.-propyl pyridazines (7).To react cool to room temperature, dilute with water (350mL), and with t-butyl methyl ether (1 * 600mL) extraction is then with isopropyl acetate (1 * 600mL) extraction.Organic layer is merged, and with the 1N aqueous sodium hydroxide solution (1 * 256mL) and water (2 * 200mL) wash.Organic layer is diluted to about 300mL.Resistates is handled with heptane (300mL).Mixture is stirred 30min cool to room temperature then under refluxing.With the solid filtering that obtains, use t-butyl methyl ether: the mixture washing in 2: 1 and the dried overnight of heptane (240mL) obtain 2-[3,5-two bromo-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-ethanol (12) (112g, 49%), is pale solid; C
15H
15Br
2ClN
2O
2(M
+) LRMS at m/z=450.Molecular weight=450.5600; Exact mass=447.9189
Step 3: preparation [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (14)
With 2-[3,5-two bromo-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-ethanol (12) (111.4g, 247mmol) at acetonitrile (223mL), methylene dichloride (343mL) and Alendronate damping fluid (the 0.67M solution of 343mL, pH=6.7) solution in room temperature with 2,2,6, (2.35g 14.83mmol) handles 6-tetramethyl--piperidino oxyradical.(44.71g, 395.5mmol) (28mL, 24.5mmol) solution in water (50mL) joins in the reaction mixture in 45min simultaneously for solution in water (135mL) and clorox with Textone then.The temperature of reaction mixture is elevated to 40 ℃ in adition process, and uses cooling bath further to raise to prevent temperature.Brown reaction mixture is stirred 30min.With the cold water refrigerative simultaneously, (28.42g, 297mmol) solution in water (86mL) is added drop-wise in the reaction mixture in 5min with sodium bisulfite.Yellow solution is diluted and extraction with methylene dichloride (223mL).Separate each layer, and (2 * 200mL) extractions, dried over sodium sulfate is filtered and vacuum concentration, obtains [3,5-two bromo-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-acetate (13) with the organic layer water.(40.56g 494mmol) joins in [3,5-two bromo-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-acetate (13) with Glacial acetic acid (549mL) and sodium acetate.Reaction mixture is heated to 120 ℃, lasts 24h.At this moment, with the reaction mixture cool to room temperature, use twice of toluene (200mL) dilution and vacuum concentration.The resistates that obtains is diluted with tetrahydrofuran (THF) (223mL) and isopropyl acetate (892mL), and water (3 * 150mL) washings.Organic layer separated and vacuum concentration to about 600mL.Add isopropyl acetate (180mL), with the mixture vacuum concentration to about 450mL.In 10min, add heptane (300mL) in batches.Mixture is stirred 15min cool to room temperature then under refluxing.With the solid filtering that obtains, be used in the 50% isopropyl acetate washing in the heptane (200mL), and under high vacuum dried overnight, obtain [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (14) (80.4g, 73%), is white solid; LRMS:C
15H
14Br
2N
2O
4(M+H) m/z=446.Molecular weight=446.0978; Exact mass=443.9320
Scheme 5: synthetic [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (19)
Embodiment 4: synthetic [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (19)
Step 1: preparation (3,5-two chloro-4-hydroxyl-phenyl)-methyl acetate (15)
(25g, 0.150mol) (2.8mL 0.015mol) handles the solution in toluene (600mL) (4-hydroxyl-phenyl)-methyl acetate that will be under room temperature, argon gas with diisobutyl amine.Reaction mixture is heated to 70 ℃ and slowly drip SULPHURYL CHLORIDE (24mL, 0.30mol) solution in toluene (75mL) in 30min.Reaction mixture is heated 1h at 70 ℃.At this moment, reaction mixture being cooled to 0 ℃ is poured on the frozen water then.The white solid that obtains is filtered and the water thorough washing.Keep filtrate.Be dissolved in solid in the ethyl acetate (500mL) and water (1 * 125mL) washing.Organic layer is separated, and dried over mgso is filtered and vacuum concentration, obtains white solid.With solid dried overnight under high vacuum, obtain (3,5-two chloro-4-hydroxyl-phenyl)-methyl acetate (15) (18.81g), be white solid.Separate the filtrate of containing water and toluene.With toluene layer water (150mL) washing, dried over mgso is filtered and vacuum concentration, obtains light yellow solid.Solid is formed slurries in the hexane solution of 10% ethyl acetate, filter and use the hexane thorough washing.With solid dried overnight under high vacuum, obtain (3,5-two chloro-4-hydroxyl-phenyl)-methyl acetate (15) (10.5g), be white solid (twice productive rate is 83%); EI (+)-HRMS m/z:C
9H
8Cl
2O
3(M
+) calculated value 233.9850, actual measurement 233.9839.Molecular weight=235.0683; Exact mass=233.9850
Step 2: preparation 2,6-two chloro-4-(2-hydroxyl-ethyl)-phenol (16)
Will being cooled under argon gas-10 ℃ (3,5-two chloro-4-hydroxyl-phenyl)-methyl acetate (15) (15.7g, 67.09mmol) solution in anhydrous tetrahydro furan (600mL), by slow dropping 1M lithium aluminum hydride at tetrahydrofuran (THF) (67.1mL, 67.1mmol) in solution, handle.After adding is finished, reaction mixture is stirred 5min, and react-10 ℃ of quenchers by the Rochelle's salt solution (80mL) of dropping 10%.Reaction suspension is stirred 10min.In suspension, add ethyl acetate (100mL) then.Filtering mixt then.(2 * 500mL) wash with ethyl acetate with solid.Separate organic layer.(2 * 200mL) extract water layer with ethyl acetate.Wash with the organic layer merging and with 0.1N aqueous hydrochloric acid, water and saturated sodium-chloride water solution.With the organic layer dried over mgso, filter and concentrate, obtain first solid product.The solid that obtains placed under high vacuum spend the night.By adding the 1N aqueous hydrochloric acid water layer is acidified to pH=5 then, and (3 * 200mL) extract once more with ethyl acetate.With organic layer merging and water and saturated sodium-chloride water solution washing.With the organic layer dried over mgso, filter and concentrate.The solid that obtains placed under high vacuum spend the night, obtain 2,6-two chloro-4-(2-hydroxyl-ethyl)-phenol (16) (13.9g, 100%); LRMS:C
8H
8Cl
2O
2(M
+) m/z=207.Molecular weight=207.0578; Exact mass=205.9901
Step 3: preparation 2-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-ethanol (17)
(6.5g 57.8mmol) handles 2,6-two chloro-4-(2-hydroxyl-ethyl)-phenol (16) (12.5g, 60.2mmol) mixture in N,N-dimethylacetamide (28mL) with potassium tert.-butoxide under room temperature, nitrogen.Suspension is heated to 100 ℃ and stir until forming solution.Then with reactant with 3, (9.2g 48mmol) handles 6-two chloro-4-sec.-propyl pyridazines (7), then with N,N-dimethylacetamide (3mL) flushing.Reaction mixture is stirred 24h at 135 ℃.To react cool to room temperature, dilute with water (30mL), and with t-butyl methyl ether (1 * 60mL) extraction is then with isopropyl acetate (1 * 60mL) extraction.Organic layer is merged, with the 1N aqueous sodium hydroxide solution (1 * 25mL) and water (2 * 25mL) wash.Separate organic layer and be diluted to the volume of about 30mL.(30mL) handles this solution with heptane.Mixture is stirred 30min cool to room temperature then under refluxing.With the solid filtering that obtains, with ether washing and dried overnight, obtain 2-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-ethanol (17) (7.5g, 44%), be white solid; LRMS:C
15H
15Cl
3N
2O
2(M+H) m/z=363.Molecular weight=361.6580; Exact mass=360.0199
Step 4: preparation [3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-acetate (18)
With 2-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-ethanol (17) (8.4g, 23.2mmol) solution in acetone (270mL) handles by slowly dripping Jones reagent (the 2.7M solution of 34.8mL is via the standard method preparation) at-4 ℃.The red reaction mixture that obtains is stirred 1h at-3 to 0 ℃.With the red reaction mixture of Virahol quencher.The green suspension that obtains is filtered by C salt, and with C salt ethyl acetate (600mL) thorough washing.With filtrate water (600mL) and saturated sodium-chloride water solution (300mL) washing.Organic layer is separated, and dried over mgso is filtered and is concentrated.The solid vacuum-drying that obtains is spent the night, obtain [3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-acetate (18) (8.3g, 95%), be white solid; LRMS:C
15H
15Cl
3N
2O
3(M
+) m/z=377.Molecular weight=377.6574; Exact mass=376.0148
Step 5: preparation [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (19)
With Glacial acetic acid (200mL), sodium acetate (6.1g, 74.4mmol) and [3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-acetate (18) (8.3g, mixture heating up to 125 21.96mmol) ℃ are lasted 24h.With reaction mixture cool to room temperature and concentrated.The resistates that obtains is diluted with methylene dichloride (200mL), and water (150mL) washing.Separate organic layer.In resistates, add in batches hexane (3 * 200mL), vacuum concentration subsequently.The semisolid that obtains is used ether dilution, the scraping of minimum and formed slurries.The white solid that obtains is filtered, with the cold diethyl ether washing and under high vacuum dried overnight, obtain [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (19) (5.1g, 65%), be white solid; LRMS:C
15H
14Cl
2N
2O
4(M
+) m/z=357.Molecular weight=357.1958; Exact mass=356.0331
Scheme 6: synthetic [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-propionic acid (23)
Embodiment 5: synthetic 3-[3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-propionic acid (23)
Step 1: preparation 2,6-two bromo-4-(3-hydroxyl-propyl group)-phenol (20)
With 4-(3-hydroxyl-propyl group)-phenol (10g, 65.7mmol) bromine (7.4mL, 144.5mmol) solution-treated in Glacial acetic acid (7.3mL) of the solution in Glacial acetic acid (73.8mL).With reaction mixture in stirred overnight at room temperature.Under vacuum, remove and desolvate.With the resistates that obtains with toluene (37mL) dilution and with solvent vacuum concentration once more.The resistates that obtains is dissolved in the tetrahydrofuran (THF) (46mL), and adds 4N aqueous sodium hydroxide solution (64mL), then add entry (27.5mL).To be reflected at stirring at room 2.5h, and by adding concentrated hydrochloric acid (14mL) with pH regulator to 5.Separate each layer (bottom is a product).With methyl tertiary butyl ether (3 * 100mL) aqueous layer extracted.Organic layer is merged, and dried over sodium sulfate is filtered and vacuum concentration.With the resistates that obtains by using the column chromatography purifying of silica gel, with 1: 1 ethyl acetate: the hexane solution wash-out.Collect required fraction and vacuum concentration.With the oily matter dried overnight under high vacuum that obtains, obtain 6-two bromo-4-(3-hydroxyl-propyl group)-phenol (20) (20.2g, 99%), be pink oily matter; LRMS:C
9H
10Br
2O
2(M-H) m/z=309.Molecular weight=309.9869; Exact mass=307.9048
Step 2: preparation 3-[3,5-two bromo-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-third-1-alcohol (21)
Under room temperature, nitrogen, (1.74g 15.48mmol) handles 2,6-two bromo-4-(3-hydroxyl-propyl group)-phenol (20) (5.0g, 16.3mmol) mixture in N,N-dimethylacetamide (8mL) with potassium tert.-butoxide.Suspension is heated to 100 ℃, lasts 15min, color becomes brown.Add 3 in suspension, (2.47g 12.9mmol), and stirs 24h with reactant at 140 ℃ to 6-two chloro-4-sec.-propyl pyridazines (7).With the reactant cool to room temperature, dilute with water (180mL) and with ethyl acetate (3 * 100mL) extraction.Organic layer is merged, and (1 * 150mL) washing is then with saturated sodium-chloride water solution (1 * 150mL) washing with the 1N aqueous sodium hydroxide solution.With the organic layer dried over sodium sulfate, filter and concentrate.The resistates that obtains by flash chromatography (Biotage 40M) purifying is with the hexane solution of 15% ethyl acetate, then with the hexane solution of 25% ethyl acetate, use the hexane solution wash-out of 50% ethyl acetate subsequently.Collect required fraction and vacuum concentration.The solid that obtains is formed slurries and filtration in cold acetonitrile.Then with the solid isopropyl acetate: 1: 1 mixture (20mL) dilution of methyl tertiary butyl ether.With mixture heating up to the cool to room temperature then that refluxes.The decantation solvent.Solid is formed slurries in heptane, filter and dried overnight under high vacuum.Filtrate is concentrated.Then with the solid isopropyl acetate that obtains: 1: 1 mixture (20mL) dilution of methyl tertiary butyl ether.With mixture heating up to the cool to room temperature then that refluxes.The decantation solvent forms slurries and filtration with solid in heptane, obtain second batch of solid product, with its dried overnight under high vacuum.Solid is merged, obtains 3-[3,5-two bromo-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-third-1-alcohol (21) (1.48g, 20%), be white solid; LRMS:C
16H
17Br
2ClN
2O
2(M+H) m/z=465.Molecular weight=464.5871; Exact mass=461.9345
Step 3: preparation 3-[3,5-two bromo-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-propionic acid (22).
Adopt and embodiment 4, similar method described in the step 4 prepares this compound, difference is to use 3-[3,5-two bromo-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-propyl alcohol (21) replacement 2-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-ethanol (17), obtain 3-[3,5-two bromo-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-propionic acid (22) (95%), be white solid; EI (+)-HRMS m/z:C
16H
15Br
2ClN
2O
3(M+H) calculated value 476.9211, actual measurement 476.9210.Molecular weight=478.5706; Exact mass=475.9138
Step 4: preparation 3-[3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-propionic acid (23)
With Glacial acetic acid (16.7mL), sodium acetate (480mg, 5.85mmol) and [3,5-two bromo-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-propionic acid (22) (800mg, mixture heating up to 120 1.67mmol) ℃ are lasted 24h.With reaction mixture cool to room temperature and concentrated.Become alkalescence to pH=9 with the dilution of the resistates water (200mL) that obtains and by adding the 1N aqueous sodium hydroxide solution.(1 * 100mL) extracts and abandons ethyl acetate with ethyl acetate with this solution.By adding the 1N aqueous hydrochloric acid, water layer is acidified to pH=3.(3 * 100mL) extract with ethyl acetate with water layer.Organic layer is merged, and dried over sodium sulfate is filtered and vacuum concentration.The solid that obtains is formed slurries in ethyl acetate (20mL).In this mixture, add heptane (20mL).Then with the volume of solvent vacuum concentration to about 20mL.With this solid filtering and with 1: 1 ethyl acetate: n-heptane solution (2 * 10mL) washings.Solid is dry under high vacuum, obtain [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-propionic acid (23) (553mg, 72%), be pale solid; LRMS:C
16H
16Br
2N
2O
4(M+H) m/z=461.Molecular weight=460.1249; Exact mass=457.9477
Scheme 7: synthetic [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl amino]-acetate (26)
Embodiment 6: synthetic [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl amino]-acetate (26)
Step 1: preparation 5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-aniline (24)
Will be under room temperature, argon gas 3,6-two chloro-4-sec.-propyl pyridazine (7) (5.4g, 28mmol) the 4-amino-2 of the solution in anhydrous dimethyl sulfoxide (20mL), 6-chlorophenesic acid (5.0g, 28mmol), Anhydrous potassium carbonate (15.6g, 112mmol) and cupric iodide (I) (3.2g 16.8mmol) handles.Reaction mixture is heated to 90 ℃, lasts 24h.Then with the reaction mixture cool to room temperature and be poured on the water (1L).With the 1N aqueous hydrochloric acid solution is adjusted to pH=8.(1 * 500mL) dilutes, and two-phase is filtered on C salt with ethyl acetate with water layer.Separate organic layer.C salt is washed with ethyl acetate.Water layer is used ethyl acetate (1 * 500mL) extraction once more.Then with the organism saturated sodium-chloride water solution (1 * 400mL) washing, dried over mgso, filtration and the vacuum concentration that merge.The resistates that obtains is dissolved in the chloroform and, is used in the 10-15% eluent ethyl acetate in the sherwood oil by using the column chromatography purifying of silica gel.Collect required fraction and vacuum concentration.The solid that obtains is formed slurries in ether, filter, and wash with cold diethyl ether.With the filtrate vacuum concentration.Solid with ether dilution and filtration, is obtained second batch of product.This product contains the unwanted isomer of trace.It is formed slurries and filtration once more in ether,
1H NMR is shown as pure required isomer.Concentrated filtrate obtains the 3rd batch of product in an identical manner.60% ether that filtrate is concentrated and is used in the sherwood oil dilutes.Under scraping, add sherwood oil and solid crystal.Collect solid, be used in the 60% ether flushing in the sherwood oil.
1H NMR shows that the 4th batch of solid product is pure required isomer.Four batches of pure solid products are merged and under high vacuum dried overnight, obtain 5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-aniline (24) (4.7g, 50%), be pale solid; EI (+)-HRMS m/z:C
13H
12Cl
3N
3O (M-H) calculated value 331.0046, actual measurement 331.0056.Molecular weight=332.6191; Exact mass=331.0046
Step 2:6-(4-amino-2,6-two chloro-phenoxy groups)-4-sec.-propyl-2H-pyridazin-3-one (25)
With Glacial acetic acid (30mL), sodium acetate (860mg, 10.48mmol) and 5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-aniline (24) (1.0g, mixture heating up to 100 3.0mmol) ℃ are lasted 24h.With the reaction mixture cool to room temperature, stir 2d and concentrate then.The resistates water (200mL) that obtains is diluted, and be basified to pH=9 by adding the 1N aqueous sodium hydroxide solution.(1 * 250mL) extracts with ethyl acetate with this suspension.By adding concentrated hydrochloric acid water layer is acidified to pH=5.(1 * 250mL) extracts water layer with ethyl acetate.Organic layer is merged, and dried over mgso is filtered and vacuum concentration.With the oily matter that obtains with methyl alcohol (20mL) dilution and with 1N aqueous sodium hydroxide solution (20mL, 20mmol) processing.Reaction mixture is heated to 120 ℃, lasts 24h.With the reaction mixture cool to room temperature and with the solvent vacuum concentration.Extract with resistates water (100mL) dilution and with ethyl acetate (200mL).Ethyl acetate layer is washed with water that contains 1N aqueous hydrochloric acid (to pH=5) and saturated sodium-chloride water solution, and dried over mgso is filtered and vacuum concentration.Resistates is dissolved in the chloroform, and, uses 1: 1 ethyl acetate that contains 0.5% Glacial acetic acid: the hexane solution wash-out by using flash chromatography (Biotage 40L) purifying of silica gel.Collect required fraction, vacuum concentration and under high vacuum in 37 ℃ of dryings.With solid ether (～form slurries 10mL) and in the sherwood oil (10mL).Solid at stirring at room 20min, is filtered and fully washes with sherwood oil.Solid is dry under high vacuum, obtain 6-(4-amino-2,6-two chloro-phenoxy groups)-4-sec.-propyl-2H-pyridazin-3-one (25) (538mg, 57%), be pale solid.LRMS：C
13H
13Cl
2N
3O
2(M
+)m/z＝314。Molecular weight=314.1735; Exact mass=313.0385
Step 3: preparation [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl amino]-acetate (26)
With (the 4-amino-2 of the 6-under the room temperature, 6-two chloro-phenoxy groups)-4-sec.-propyl-2H-pyridazin-3-one (25) (500mg, 1.59mmol) solution in methylene dichloride (22mL) and methyl alcohol (22mL) is with a glyoxylic acid (292mg, 3.17mmol), Glacial acetic acid (0.10mL, 1.74mmol), the sal epsom of little spear and cyano group borohydride (Argonaut Technologies Inc.MP-(CN) BH of resin-bonded
3, 0.97g 2.39mmol) handles.Reaction mixture is heated to 50 ℃, lasts 24h.With the reaction mixture cool to room temperature, filter and wash then with chloroform by C salt.In filtrate, add 1N aqueous hydrochloric acid (150mL).The mixture that obtains is stirred 30min.Separate organic layer.With chloroform (100mL) aqueous layer extracted.Organic layer is merged, add methyl alcohol (10mL) with the dissolving insolubles, and, filter and vacuum concentration the organic layer dried over mgso.The solid that obtains is diluted with ether (3mL) formation slurries and with sherwood oil (10mL).Mixture is stirred 45min.By solid collected by filtration, and wash with sherwood oil.TLC shows the impurity that has a spot of higher Rf.With solid by using flash chromatography (Biotage 40L) purifying of silica gel, with 100% ethyl acetate, then be used in 0.4% Glacial acetic acid wash-out in the ethyl acetate.Collect required fraction and vacuum concentration.With solid with 1: 1 methylene dichloride: hexane dilution and vacuum concentration.Solid is formed slurries in sherwood oil, filter, wash and dried overnight under high vacuum with sherwood oil, obtain [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl amino]-acetate (26) (98.7mg, 17%), is white solid; LRMS:C
15H
15Cl
2N
3O
4(M
+) m/z=372.Molecular weight=372.2105; Exact mass=371.0440
Scheme 8: synthetic N-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl-oxalic acid (29)
Embodiment 7: synthetic N-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-oxalic acid (29)
Step 1: preparation N-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-methyl oxalate (27)
(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-((2.5mL 144mmol) handles the N-diisopropylethylamine aniline (24) for 2.0g, 6mmol) the solution N in anhydrous tetrahydro furan (28mL) with the two chloro-4-of the 5-under the room temperature.Reaction mixture is cooled to 0 ℃ uses methyl oxalyl chloride (0.66mL, 72mmol) processing then.Reaction mixture is warming to room temperature and stirs 3h.Reaction mixture is poured on water (1L) upward and with ethyl acetate (300mL) and saturated sodium-chloride water solution (100mL) to be diluted.Separate organic layer.(2 * 300mL) extract water layer once more with ethyl acetate.Organic layer merged and with the 1N aqueous hydrochloric acid (1 * 150mL) and saturated sodium-chloride water solution (1 * 150mL) washs, dried over mgso, filtration and vacuum concentration.The solid that obtains is dissolved in the ethyl acetate that contains methyl alcohol, and, is used in the 15-30% eluent ethyl acetate in the sherwood oil by silica gel chromatography.With required fraction vacuum concentration.The solid that obtains is dry under high vacuum, obtain N-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-methyl oxalate (27) (1.91g, 76%), be white solid; EI (+)-HRMS m/z:C
16H
14Cl
3N
3O
4(M+H) calculated value 418.0123, actual measurement 418.0123.Molecular weight=418.6667; Exact mass=417.0050
Step 2: preparation N-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-oxalic acid (28)
With 0 ℃ N-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-(1.87g, 4.47mmol) (8.95mL 8.95mmol) handles the suspension in methyl alcohol (35mL) methyl oxalate (27) with the 1N aqueous sodium hydroxide solution.Reaction mixture is warming to room temperature and stirs 2h.With the solvent vacuum concentration.Resistates water (500mL) dilutes, and by adding the 1N aqueous hydrochloric acid mixture is acidified to pH=1-2.(2 * 250mL) extract with ethyl acetate with mixture.Separate organic layer, use dried over mgso, filter and concentrate.The solid that obtains is spent the night in high vacuum dry, obtains N-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-oxalic acid (28) (1.77g, 98%), be white solid; EI (+)-HRMS m/z:C
15H
12Cl
3N
3O
4(M+H) calculated value 403.9966, actual measurement 403.9968.Molecular weight=404.6396; Exact mass=402.9893
Step 3: preparation N-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-oxalic acid (29)
With Glacial acetic acid (55mL), sodium acetate (1.2g, 14.7mmol) and N-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-(1.7g, mixture heating up to 100 4.2mmol) ℃ are lasted 24h to oxalic acid (28).With reaction mixture cool to room temperature and vacuum concentration.With solid water (50mL) dilution that obtains.By adding Glacial acetic acid mixture is acidified to pH=3.With solid filtering, water fully washes and is dry on funnel.With solid at 1: 1: 2 isopropyl acetate: methyl tertiary butyl ether: form slurries in the hexane (3mL), be heated to backflow then.With mixture cooling and filtration.TLC detects a spot of impurity.Solid is formed slurries and filtration in isopropyl acetate (10mL).With the pure solid dry 24h under high vacuum that obtains, then in vacuum oven in 80 ℃ of dry 24h, obtain N-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-oxalic acid (29) (0.91g, 56%), be white solid; EI (+)-HRMS m/z:C
15H
13Cl
2N
3O
5(M+H) calculated value 386.0305, actual measurement 386.0308.Molecular weight=386.1940; Exact mass=385.0232
Scheme 9: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (31)
Embodiment 8: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (31)
Step 1: preparation 2-cyano group-2-{[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-hydrazono-}-ethanoyl)-urethanum (30)
(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-aniline (24) (134mg, 0.42mmol) handle with concentrated hydrochloric acid (2.8mL) by the suspension in water (5.6mL) with 5-two chloro-4-.Reaction mixture is cooled to 0 ℃, and (36.5mg, 0.529mmol) solution in water (0.2mL) is handled under the reaction mixture surface, then water (0.2mL) flushing to use SODIUMNITRATE then.Reaction mixture is stirred 30min at 0 ℃, form solution.In being equipped with the separation flask of magnetic stirring apparatus, add N-cyano group acetylamino ethyl formate (73mg, 0.46mol), water (9.4mL) and pyridine (2.8mL).This reaction mixture is cooled to 0 ℃, and will filters fast and pour in second reaction mixture from the solution of first reaction.Form orange throw out, suspension is stirred 30min at 0 ℃.With solid filtering, the water flushing is then washed with sherwood oil.With solid in vacuum oven in 80 ℃ of dried overnight, obtain 2-cyano group-2-{[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-hydrazono-}-ethanoyl)-urethanum (30) (156mg, 76%), is orange solids; EI (+)-HRMS m/z:C
19H
18Cl
2N
6O
5(M+H) calculated value 481.0789, actual measurement 481.0790.Molecular weight=481.2985; Exact mass=480.0716
Step 2: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (31)
With 2-cyano group-2-{[3; 5-two chloro-4-(5-sec.-propyl-6-oxo-1; 6-dihydro-pyridazine-3-base oxygen base)-phenyl]-hydrazono-}-ethanoyl)-urethanum (30) (3.49g; 7.17mmol) (2.94g 35.8mmol) handles with sodium acetate in room temperature for mixture in Glacial acetic acid (72mL).Reaction mixture is heated to 120 ℃, lasts 1.5h.At this moment, reaction is cooled to 0 ℃, water (220mL) dilution and stirring 30min.With the solid filtering that obtains, (3 * 100mL) flushings are then with sherwood oil (3 * 100mL) flushings for water.With the dry 30min of solid air.Then solid is diluted with hot acetonitrile (250mL).The red mixture that obtains is handled with neutral decolorizing charcoal, filtered and wash by C salt, until there not being UV active substance wash-out to come out with acetonitrile (1L).With the yellow filtrate concentrating under reduced pressure.The solid that obtains is ground cooling 15min, water (100mL) dilution and filtration with hot acetonitrile (50mL).Use hot acetonitrile (10mL) to grind once more solid, filter and wash with acetonitrile, water and sherwood oil.Collect solid, dried overnight under high vacuum, then in vacuum oven in 80 ℃ of dried overnight, obtain 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (31) (1.91g, 61%) is yellow solid; EI (+)-HRMS m/z:C
17H
12Cl
2N
6O
4(M+H)
+Calculated value 435.0370, actual measurement 435.0368.Molecular weight=435.2290; Exact mass=434.0297
Scheme 10: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-2H-[1,2,4] triazine-3,5-diketone (33)
Embodiment 9:2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-2H-[1,2,4] triazine-3,5-diketone (33)
Step 1: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-carboxylic acid (32)
With 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (31) (136mg, 0.312mmol) handle with concentrated hydrochloric acid (0.345mL) by the mixture in Glacial acetic acid (3.0mL).Reaction mixture is heated to 120 ℃, lasts 24h.Still there is raw material in the LC/MS demonstration.Add other concentrated hydrochloric acid (0.34mL).Reaction mixture is heated to 120 ℃ of 24h once more.With reaction mixture cool to room temperature and water (50mL) dilution.At this moment, make reactant become alkalescence by adding the 1N aqueous sodium hydroxide solution, and extract with ether (100mL).Abandon organic layer.(2 * 100mL) extract with the water layer acidifying and with ethyl acetate by adding the 1N aqueous hydrochloric acid.Organic layer is merged, with saturated sodium-chloride water solution washing, dried over mgso, filter and vacuum concentration, obtain 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-and phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-carboxylic acid (32) (111mg, 78%), be orange solids, with it without using with being further purified; LRMS:C
17H
13Cl
2N
5O
6(M
+) m/z=454.Molecular weight=454.2291; Exact mass=453.0243
Step 2: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-2H-[1,2,4] triazine-3,5-diketone (33)
With 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-carboxylic acid (32) (102mg, 0.22mmol) and mixture heating up to the 170 ℃ 1h of Thiovanic acid (2.2mL).At this moment, with the reaction mixture cool to room temperature, water (120mL) dilutes and extracts with ethyl acetate (100mL).Separate organic layer, and with saturated sodium bicarbonate aqueous solution (2 * 100mL) and saturated sodium-chloride water solution (100mL) wash dried over mgso, filtration and vacuum concentration.The solid that obtains is dissolved in the methylene dichloride,,, then is used in the required product of 0.2% Glacial acetic acid wash-out in the ethyl acetate with 100% eluent ethyl acetate impurity by using flash chromatography (Biotage 40S) purifying of silica gel.Collect required fraction and vacuum concentration.The solid that obtains is formed slurries in hot methanol (2mL), filter and wash with sherwood oil.With solid in vacuum oven in 80 ℃ of dryings, obtain 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-2H-[1,2,4] triazine-3,5-diketone (33) (21.4mg, 23%) is yellow solid; EI (+)-HRMS m/z:C
16H
13Cl
2N
5O
4(M+) calculated value 410.0418, actual measurement 410.0419.Molecular weight=410.2191; Exact mass=409.0345
Scheme 11 synthetic [3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (37)
Embodiment 10: synthetic [3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (37)
Step 1: preparation acetate 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-ethyl ester (34)
With 2-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-(500mg, 1.38mmol) (230mg 2.8mmol) handles, and is heated to 114 ℃ the solution in Glacial acetic acid (5mL) ethanol (17), lasts 24h with sodium acetate.At this moment, with reaction mixture cool to room temperature and vacuum concentration.The resistates that obtains is washed with methylene dichloride (25mL) dilution and water (10mL).Separate organic layer and wash with saturated sodium bicarbonate aqueous solution (10mL).Combining water layer and extract with methylene dichloride (10mL).Organic layer is merged, use dried over sodium sulfate, filter, concentrate, and dried overnight under high vacuum obtains acetate 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-ethyl ester (34) (531mg, 100%), be white solid; LRMS:C
17H
18Cl
2N
2O
4(M
+) m/z=385.Molecular weight=385.2500; Exact mass=384.0644
Step 2: preparation acetate 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-ethyl ester (35)
With acetate 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-ethyl ester (34) (531mg, 1.38mmol), salt of wormwood (280mg, 2.03mmol) and methyl-iodide (2mL, mixture 32.1mmol) is warming to 40 ℃, lasts 2h.Add other methyl-iodide (1mL, 16.05mmol), then insert salt of wormwood (140mg, 1.01mmol).Mixture is heated 2h then at stirring at room 24h at 40 ℃.Concentrated reaction mixture distributes the resistates that obtains between ethyl acetate (50mL) and water (25mL).Water layer is extracted once more with ethyl acetate (25mL).Organic layer is merged, and dried over sodium sulfate is filtered and is concentrated.The resistates that obtains is dissolved in the hexane solution of 25% ethyl acetate, and uses flash chromatography (Biotage 40S) purifying of silica gel, with the hexane solution wash-out of 25-50% ethyl acetate.Collect required fraction and vacuum concentration.The solid that obtains is dry under high vacuum, obtain 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-ethyl ester (35) (395mg, 72%), be clarification oily matter; LRMS:C
18H
20Cl
2N
2O
4(M
+) m/z=399.Molecular weight=399.2771; Exact mass=398.0800
Step 3: preparation 6-[2,6-two chloro-4-(2-hydroxyl-ethyl)-phenoxy group]-4-sec.-propyl-2-methyl-pyridazin-3-one (36)
With 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-(390mg, 0.97mmol) solution in methyl alcohol (4mL) is at room temperature used 1N aqueous sodium hydroxide solution (1.0mL, 1.0mmol) processing to ethyl ester (35).Reaction mixture is stirred 24h vacuum concentration then.The resistates that obtains is washed with methylene dichloride (35mL) dilution and with saturated sodium-chloride water solution (20mL).Separate water layer and extract once more with methylene dichloride (25mL).Organic layer is merged, use dried over sodium sulfate, filter and concentrate.The solid that obtains is dry under high vacuum, obtain 6-[2,6-two chloro-4-(2-hydroxyl-ethyl)-phenoxy group]-4-sec.-propyl-2-methyl-pyridazin-3-one (36) (350mg, 97%), be white solid, with it without use with being further purified.Molecular weight=357.2395; Exact mass=356.0694
Step 4: preparation [3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (37)
With 6-[2,6-two chloro-4-(2-hydroxyl-ethyl)-phenoxy group]-4-sec.-propyl-2-methyl-pyridazin-3-one (36) (330mg, 0.92mmol) handle by slowly dripping Jones reagent (the 2.7M solution of 0.51mL) at 10 ℃ by the solution in acetone (5mL).The red reaction mixture that obtains is stirred 30min at 10 ℃.Then with the reaction mixture vacuum concentration.The resistates that obtains is diluted with ethyl acetate (25mL) and water (20mL), and handle with sodium bisulfite (100mg).Mixture vibration with obtaining becomes green by redness.Separate water layer, and extract once more with ethyl acetate (25mL).Organic layer is merged, and wash with saturated sodium-chloride water solution.Separate organic layer, dried over sodium sulfate is filtered and vacuum concentration.The solid that obtains is spent the night from re-crystallizing in ethyl acetate and vacuum-drying, obtain [3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (37) (70mg, 19%), be white solid; EI (+)-HRMS) m/z:C
16H
16Cl
2N
2O
4(M+H)
+Calculated value 371.0560, actual measurement 371.0561.Molecular weight=371.2229; Exact mass=370.0487
Scheme 12: synthetic [3,5-two bromo-4-(1-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (42):
Embodiment 11: synthetic [3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (42)
Step 1: preparation 2-[3,5-two bromo-4-(6-chloro-pyridazine-3-base oxygen base)-phenyl]-ethanol (38):
Adopt and embodiment 3, the similar method described in the step 2 prepares this compound, and difference is to use 3, and 6-two chloro-pyridazines replace 3,6-two chloro-4-sec.-propyl pyridazines (7).Reactant is heated 3.5h at 140 ℃.Handle (work up) and be different from embodiment 3, step 2.Reaction mixture is under agitation slowly joined saturated sodium-chloride water solution.With the mixture dichloromethane extraction.Wash with the organic layer merging and with saturated sodium-chloride water solution, dried over sodium sulfate is filtered, and concentrates.The oily matter that obtains is dissolved in the methylene dichloride, by using flash chromatography (Biotage) purifying of silica gel, with the hexane solution wash-out of 10-40% ethyl acetate.Collect required fraction and vacuum concentration, obtain oily matter, it is dry under high vacuum, obtain 2-[3,5-two bromo-4-(6-chloro-pyridazine-3-base oxygen base)-phenyl]-ethanol (38) (51%), be amber oily thing; LRMS:C
12H
9Br
2ClN
2O
2(M
+) m/z=409.Molecular weight=408.4787; Exact mass=405.8719
Step 2: preparation acetate 2-[3,5-two bromo-4-(6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-ethyl ester (39)
Adopt and embodiment 10, this compound of similar method described in the step 1, difference is to use 2-[3,5-two bromo-4-(6-chloro-pyridazine-3-base oxygen base)-phenyl]-ethanol (38) replacement 2-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-phenyl]-ethanol (17), obtain acetate 2-[3,5-two bromo-4-(6-oxos-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-ethyl ester (39) (92%), be colorless oil; LRMS:C
14H
12Br
2N
2O
4(M+H) m/z=433.Molecular weight=432.0707; Exact mass=429.9164
Step 3: preparation acetate 2-[3,5-two bromo-4-(1-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-ethyl ester (40)
Adopt and embodiment 10, similar method described in the step 2 prepares this compound, difference is to use isopropyl iodide to replace methyl-iodide and uses acetate 2-[3,5-two bromo-4-(6-oxos-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-ethyl ester (39) replacement acetate 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-ethyl ester (34).Method is similar, but difference is reactant is heated to 50 ℃, lasts 24h.By using the column chromatography of silica gel, with hexane solution to 100% eluent ethyl acetate of 10% ethyl acetate, purified product, obtain 2-[3,5-two bromo-4-(1-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-ethyl ester (40) (79%), be white solid; LRMS:C
17H
18Br
2N
2O
4(M+CH
3CN+H) m/z=516.Molecular weight=474.1520; Exact mass=471.9633
Step 4: preparation 6-[2,6-two bromo-4-(2-hydroxyl-ethyl)-phenoxy group]-2-sec.-propyl-pyridazin-3-one (41)
With 2-[3,5-two bromo-4-(1-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-(85mg, 0.18mmol) (90 μ L 0.18mmol) handle the solution in methyl alcohol (0.5mL) ethyl ester (40) with the 2N potassium hydroxide aqueous solution in room temperature.Reaction mixture is heated to 55 ℃, stirs 1h concentrating under reduced pressure then.The resistates that obtains is diluted with methylene dichloride (5mL) and water (2 * 3mL) washings.Water layer extracts once more with methylene dichloride (5mL).Organic layer is merged, use dried over sodium sulfate, filter, and concentrate.The solid that obtains is dry under high vacuum, obtain 6-[2,6-two bromo-4-(2-hydroxyl-ethyl)-phenoxy group]-2-sec.-propyl-pyridazin-3-one (41) (77mg, 100%), be white solid, with it without use with being further purified; LRMS:C
15H
16Br
2N
2O
3(M+CH
3CN+H) m/z=474.Molecular weight=432.1144; Exact mass=429.9528
Step 5: preparation [3,5-two bromo-4-(1-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (42)
Adopt and embodiment 10, similar method described in the step 4 prepares this compound, difference is to use 6-[2,6-two bromo-4-(2-hydroxyl-ethyl)-phenoxy group]-2-sec.-propyl-pyridazin-3-one (41) replacement 6-[2,6-two chloro-4-(2-hydroxyl-ethyl)-phenoxy group]-4-sec.-propyl-2-methyl-pyridazin-3-one (36).By using the flash chromatography (Biotage) of silica gel, with the hexane solution wash-out of 50% ethyl acetate, this product of purifying.Collect required fraction and vacuum concentration, obtain solid, it is dry under high vacuum, obtain [3,5-two bromo-4-(1-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate (42), be pale solid (40mg, 52%); EI (+)-HRMS m/z:C
15H
14Br
2N
2O
4(M+H)
+Calculated value 444.9393, actual measurement 444.9392.Molecular weight=446.0978; Exact mass=443.9320
Scheme 13 Synthetic 2s-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (48):
Embodiment 12: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (48)
Step 1: preparation cyano group-(2,6-two chloro-4-nitro-phenyl)-ra-butyl acetate (43)
With 25 ℃ 1,2,3-three chloro-5-oil of mirbane (50.33g, 222.26mmol) at N, solution in the dinethylformamide (220mL) with 2-valeronitrile yl acetate (33mL, 230.72mmol) and salt of wormwood (61.44g, 444.54mmol) processing.Reaction flask is equipped with reflux condensing tube.Be heated 50 ℃ then, last 18h.At this moment, make reaction be cooled to 25 ℃ of vacuum concentration then.Reaction mixture is dissolved in ethyl acetate (1.2L) and the water (300mL).Should the bilayer neutralization by adding 1N aqueous hydrochloric acid (250mL) and 3N aqueous hydrochloric acid (300mL).Separate each layer that obtains.(3 * 500mL) and saturated sodium-chloride water solution (250mL) washing, dried over mgso is filtered with the organism water, and vacuum concentration, obtain cyano group-(2,6-two chloro-4-nitro-phenyl)-ra-butyl acetate (43) (78.69g), be golden yellow brown oil.With this compound without using with being further purified.Exact mass=330.0174; Molecular weight=331.16.
Step 2: preparation (4-amino-2,6-two chloro-phenyl)-acetonitrile (44):
The solution of 25 ℃ cyano group-(2,6-two chloro-4-nitro-phenyl)-ra-butyl acetate (43) (78.69g, crude product) in ethanol (320mL) is handled with concentrated hydrochloric acid (160mL).To react the outfit reflux condensing tube and be heated to 75 ℃ then.At this moment, with the homogeneous phase solution that obtains with two hydration tin chloride (II) (225.64g, 1.0mol) batch treatments.After the adding of two hydration tin chlorides (II) is finished, reaction is warming to 110-115 ℃, stir 3h in this temperature.At this moment, reaction is cooled to 25 ℃ and uses ethyl acetate (1.5L) dilution then.The solution that obtains is neutralized with saturated aqueous sodium carbonate (1.0L) is careful.Via vacuum filtration, the thick mixture that obtains is passed through filter paper filtering, and with the ethyl acetate washing, till in filtrate, detecting less than raw material.Then filtrate is transferred to separating funnel, in separating funnel, separate each layer that obtains.With organism with the 1N aqueous hydrochloric acid (1 * 250mL), saturated aqueous sodium carbonate (1 * 250mL), 1N aqueous hydrochloric acid (1 * 250mL) and saturated sodium-chloride water solution (1 * 250mL) continuous washing.With the organism dried over mgso, filter then, and vacuum concentration.Obtain (4-amino-2,6-two chloro-phenyl)-acetonitrile (44) (25.9g, 58%) through flash chromatography (Merck silica gel 60,230-400 order, 80/20 hexane/ethyl acetate), be yellow solid; EI-HRMS m/e:C
8H
6Cl
2N
2(M
+) calculated value 199.9908, actual measurement 199.9906. exact mass=199.9908; Molecular weight=201.06.
Step 3: preparation (4-amino-2,6-two chloro-phenyl)-(6-chloro-5-sec.-propyl-pyridazine-3-yl)-acetonitrile (45):
In 500mL round-bottomed flask (careful: as to use the super large flask), with 3,6-two chloro-4-sec.-propyl pyridazines (7) (5.54g, 29.0mmol) (the 4-amino-2 of the solution in tetrahydrofuran (THF) (116mL), 6-two chloro-phenyl)-(5.81g 28.9mmol) handles acetonitrile (44).Reaction mixture is equipped with water-cooled condenser and is heated to 60 ℃.Then flask is taken out oil bath and add potassium tert.-butoxide (6.85g, 57.99mmol).With mixture heating up to 60 ℃, last 45min.To react cool to room temperature, and transfer to separating funnel, (2 * 250mL) wash with ethyl acetate (500mL) dilution and with saturated sodium-chloride water solution.Separate organic layer, use dried over mgso, and filter.In filtrate, add silica gel 60 (70-230 order) and vacuum concentration solvent.By using the flash chromatography (Biotage 75L) of silica gel, with the hexane solution wash-out of 15%-30% ethyl acetate, with the purifying mixture that obtains.Collect required fraction and vacuum concentration, obtain solid, it is dry under high vacuum, obtain (4-amino-2,6-two chloro-phenyl)-(6-chloro-5-sec.-propyl-pyridazine-3-yl)-acetonitrile (45) (7.87g, 77%), be orange foam; LRMS:C
15H
13Cl
3N
4(M+H) m/z=355.With this compound without using with being further purified.Molecular weight=355.6567; Exact mass=354.0206
Step 4: preparation 6-(4-amino-2,6-two chloro-benzyls)-4-sec.-propyl-pyridazin-3-one (46):
(6.98g 19.63mmol), the mixture heating up to 120 of water (30mL), concentrated hydrochloric acid (120mL) and Glacial acetic acid (30mL) ℃, lasts 24h with (4-amino-2,6-two chloro-phenyl)-(6-chloro-5-sec.-propyl-pyridazine-3-yl)-acetonitrile (45).At this moment, will react cool to room temperature and mixture is poured on the water (250mL).By adding the 4N aqueous sodium hydroxide solution, pH regulator is arrived neutral (pH=7).Suspension is placed water cooler 15min.With solid filtering and water and the petroleum ether that obtains.Collect solid and it is dissolved in the hot ethyl acetate.Add silica gel 60 (70-230 order) and vacuum concentration solvent.By using the flash chromatography (Biotage 75S) of silica gel, use the hexane solution wash-out of hexane solution to 50% ethyl acetate of 40% ethyl acetate that contains 0.5% Glacial acetic acid, with the purifying mixture that obtains.Collect required fraction and vacuum concentration, obtain solid, it is dry under high vacuum, obtain 6-(4-amino-2,6-two chloro-benzyls) 4-sec.-propyl-pyridazin-3-one (46) (4.65g, 76%), be pale solid; LRMS:C
14H
15Cl
2N
3O (M+H) m/z=312.Molecular weight=312.2012; Exact mass=311.0592
Step 5: preparation (2-cyano group-2-{[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-hydrazono-}-ethanoyl)-urethanum (47):
Adopt and embodiment 8, similar method described in the step 1 prepares this compound, difference is to use 6-(4-amino-2,6-two chloro-benzyls)-14-sec.-propyl-pyridazin-3-one (46) replacement 5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base oxygen base)-aniline (25), obtain (2-cyano group-2-{[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-hydrazono-}-ethanoyl)-urethanum (47), be orange solids (3.44g, 75%); EI (+)-HRMS m/z:C
20H
20Cl
2N
6O
4(M+H) the 1+ calculated value 479.0996, actual measurement 479.0997.Molecular weight=479.3262; Exact mass=478.0923
Step 6: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (48)
Adopt and embodiment 8, similar method described in the step 2 prepares this compound, difference is to use (2-cyano group-2-{[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-hydrazono-}-ethanoyl)-urethanum (47) replacement 2-cyano group-2-{[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-hydrazono-}-ethanoyl)-urethanum (30), obtain 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (48) is pale solid (1.21g, 39%); EI (+)-HRMS m/z:C
18H
14Cl
2N
6O
3(M+H) the 1+ calculated value 433.0577, actual measurement 433.0577.Molecular weight=433.2567; Exact mass=432.0504
Scheme 14: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-[1,2,4] triazine-3,5-diketone (50):
Embodiment 13: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-[1,2,4] triazine-3,5-diketone (50)
Step 1: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-carboxylic acid (49)
Adopt and embodiment 9, the similar method described in the step 1 prepares this compound, and difference is to use 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-and phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (48) replaces 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (31).In addition, when reaction is finished, with the reaction mixture dilute with water, and with the solid filtering that obtains, water, then fully wash with sherwood oil.With solid vacuum-drying, obtain 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-carboxylic acid (49) (81%) is pale solid; LRMS:C
18H
15Cl
2N
5O
5(M+H) m/z=452.Molecular weight=452.2568; Exact mass=451.0450
Step 2: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-[1,2,4] triazine-3,5-diketone (50):
With 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4, (101.5mg 0.224mmol) handles with Thiovanic acid (2.2mL) 5-tetrahydrochysene-[1,2,4] triazine-6-carboxylic acid (49).Reaction mixture with magnetic stirrer and be heated to 155 ℃, is lasted 24h.With the reaction mixture cool to room temperature, water (25mL) dilutes and extracts with ethyl acetate (25mL) then.(3 * 10mL) wash with the organic layer separation and with the 1N aqueous sodium hydroxide solution.Water layer merged and be acidified to pH=4.With the solid filtering that obtains, water, then fully wash with sherwood oil.With solid vacuum-drying, obtain two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-[1,2,4] triazine-3,5-diketone (50) (36mg, 40%), for brown solid-state; EI (+)-HRMS m/z:C
17H
15Cl
2N
5O
3(M+H) the 1+ calculated value 408.0625, actual measurement 408.0626.Molecular weight=408.2468; Exact mass=407.0552
Scheme 15 synthetic [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate (56)
Embodiment 14: synthetic [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate (56)
Step 1: preparation 6-(4-bromo-2,6-two chloro-benzyls)-4-sec.-propyl-pyridazin-3-one (51)
(0.9g, 2.88mmol) solution in Glacial acetic acid (16mL) is handled with the vitriol oil (4mL) with the 6-under the room temperature (4-amino-2,6-two chloro-benzyls)-4-sec.-propyl-pyridazin-3-one (46).(480mg, 6.96mmol) solution in water (5mL) slowly joins below the reacted surface in 10min with Sodium Nitrite.Reaction mixture is heated to 60 ℃, lasts 1h.To react cool to room temperature, and drip cupric bromide (I) (450mg, 3.14mmol) and the aqueous solution (2mL, mixture 17.68mmol) of 48% hydrogen bromide.Reaction is heated to 100 ℃, violent venting takes place in this temperature.Behind the 1h, will react cool to room temperature, upward and with ether (3 * 75mL) extract to be poured on frozen water (100mL).Ether layer is used saturated sodium bicarbonate aqueous solution (150mL) washing carefully.Organic layer is separated, use dried over mgso, filter and vacuum concentration.By using the flash chromatography of silica gel, with 4: 1 to 2: 1 ethyl acetate: the gradient elution of hexane, with the solid purifying that obtains.Collect required fraction and vacuum concentration, obtain solid, it is dry under high vacuum, obtain 6-(4-bromo-2,6-two chloro-benzyls)-4-sec.-propyl-pyridazin-3-one (51) (553mg, 51%), be pale solid; C
14H
13BrCl
2N
2LRMS-ES (+) m/z=375 of O (M+H).MW=376.0825, exact mass=373.9588
Step 2: preparation 3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-methyl benzoate (52)
With (the 4-bromo-2 of the 6-under the room temperature, 6-two chloro-benzyls)-4-sec.-propyl-pyridazin-3-one (51) (194mg, 0.516mmol) solution in acetonitrile (10mL) and methyl alcohol (2mL) is with acid chloride (II) (23.7mg, 0.106mmol), 1, two (diphenyl phosphine) propane (45.7mg of 3-, 0.111mmol) and triethylamine (360 μ L, 2.58mmol) processing.Then sealed tube is pressurized to 45psi with carbon monoxide, and is heated to 90 ℃ of 1h.To react cool to room temperature, relief pressure, and carry out the TLC of reaction mixture, this TLC show and still have raw material.(10mg) with 1, two (diphenyl phosphine) propane (20mg) of 3-join in the reaction mixture with other acid chloride (II).Sealed tube is pressurized to 45psi and is heated to 90 ℃ with carbon monoxide once more, last other 1.5h.To react cool to room temperature, relief pressure dilutes reaction mixture with ethyl acetate (100mL), and 1: 1 solution washing of water (30mL) and saturated sodium-chloride water solution (30mL).Organic layer is separated, use dried over mgso, filter and concentrate.By using the flash chromatography of silica gel, with 4: 1 to 1: 1 ethyl acetate: the gradient elution of hexane, with the residue purified that obtains.Collect required fraction and vacuum concentration, obtain solid, it is dry under high vacuum, obtain 3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-methyl benzoate (52) (183mg, 90%) are pale solid; LRMS-ES (+): C
16H
16Cl
2N
2O
3(M+H) m/z=355.MW=355.2235, exact mass=354.0538
Step 3: preparation 6-(2,6-two chloro-4-methylol-benzyls)-4-sec.-propyl-pyridazin-3-one (53)
With 25 ℃ 3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-methyl benzoate (52) (160mg, 0.45mmol) tetrahydrofuran solution (2.7mL, 2.7mmol) processing of the diisobutylaluminium hydride of 1M of the mixture in tetrahydrofuran (THF) (5mL).To be reflected at stirring at room 24h.Still there is raw material in the TLC demonstration of reactant.The tetrahydrofuran solution (1.0mL) of the diisobutylaluminium hydride of the 1M of adding additional quantity in reactant.After at room temperature stirring 30min, by adding 1: 1 mixture of saturated sodium-chloride water solution (30mL) and 2N aqueous hydrochloric acid (30mL), careful quencher reaction.(3 * 50mL) extract with ethyl acetate with mixture.Organic layer is merged, and with saturated sodium-chloride water solution (20mL) washing, dried over mgso is filtered and vacuum concentration.The solid that obtains is dry under high vacuum, obtain 6-(2,6-two chloro-4-methylol-benzyls)-4-sec.-propyl-pyridazin-3-one (53) (168mg), be brown solid, with it without use with being further purified; LRMS-ES (+): C
15H
16Cl
2N
2O
2(M+H) m/z=327.MW=327.2130, exact mass=326.0589
Step 4: preparation 6-(4-brooethyl-2,6-two chloro-benzyls)-4-sec.-propyl-pyridazin-3-one (54)
With 0 ℃ 6-(2,6-two chloro-4-methylol-benzyls)-4-sec.-propyl-pyridazin-3-one (53) (165mg, 0.45mmol in theory) solution in methylene dichloride (2mL) is with carbon tetrabromide (187mg, 0.56mmol) and triphenyl phosphine (178mg, 0.68mmol) solution-treated in methylene dichloride (2mL).Reaction mixture is stirred 30min water quencher then at 0 ℃.(3 * 50mL) extract with reactant water (20mL) dilution and with ethyl acetate.Organic layer is merged, use dried over mgso, filter and vacuum concentration.By using the flash chromatography of silica gel, with the hexane solution wash-out of 20%-45% ethyl acetate, with the oily matter purifying that obtains.Collect required fraction and vacuum concentration, obtain yellow solid, it is dry under high vacuum, obtain 6-(4-brooethyl-2,6-two chloro-benzyls)-4-sec.-propyl-pyridazin-3-one (54) (70mg, 36%), be yellow solid; LRMS-ES (+): C
15H
15BrCl
2N
2O (M+H) m/z=389.MW=390.1096, exact mass=387.9745
Step 5: preparation [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetonitrile (55)
With the sodium cyanide (270mg under the room temperature, 5.51mml) suspension in methyl-sulphoxide (2mL) is with the vitriol oil (0.1mL, 1.88mml) and 6-(4-brooethyl-2,6-two chloro-benzyls)-4-sec.-propyl-pyridazin-3-one (54) (70mg, 0.180mmol) solution-treated in methyl-sulphoxide (2mL).Reaction mixture is stirred 1h at 50 ℃ then at stirring at room 30min.To react cool to room temperature, and be poured on the saturated sodium bicarbonate aqueous solution (50mL), ethyl acetate (3 * 75mL) extractions are used in water (20mL) dilution then.Organic layer is merged, and with saturated sodium-chloride water solution (50mL) washing, dried over mgso is filtered, and vacuum concentration.The oily matter that obtains is dry under high vacuum, obtain [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetonitrile (55), be orange (supposition 0.180mmol), with it without use with being further purified.
Step 6: preparation [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate (56)
The mixture heating up of [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetonitrile (55) (supposition 0.180mmol) in concentrated hydrochloric acid (4mL) lasted 24h to refluxing.With the reaction mixture cool to room temperature, wash with ethyl acetate (75mL) dilution and with saturated sodium-chloride water solution (20mL) and water (10mL).Water layer is merged, and extract with ethyl acetate (50mL).Organic layer is merged, use dried over mgso, filter, and vacuum concentration.With the oily matter that obtains with HPLC (acetonitrile/water that contains 0.1% trifluoroacetic acid) purifying.Collect required fraction, it is concentrated and lyophilize.By using the flash chromatography of silica gel, be used in 10% methanol-eluted fractions in the methylene dichloride, with the solid purifying that obtains.Collect required fraction and vacuum concentration, obtain solid, it is dry under high vacuum, obtain 3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate (56) (8.6mg, 2 steps were 13%), be white solid; EI (+)-HRMS m/z:C
16H
16Cl
2N
2O
3(M+H)
+Calculated value 355.0611, actual measurement 355.0611.MW=355.2235, exact mass=354.0538
Scheme 16: synthetic [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate (64)
Embodiment 15: synthetic [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate (64)
Step 1: preparation 3,5-two bromo-4-brooethyl-methyl benzoate (57)
With 3, (5g, 16.24mmol) (3.6g, 20.23mmol) with 2, (0.56g 3.410mmol) handles 2 '-azobis isobutyronitrile the solution in tetracol phenixin (50mL) 5-two bromo-methyl 4 methylbenzoates with N-bromine succinic diamide.Reaction mixture is heated to backflow 24h.To react cool to room temperature and vacuum concentration.The mixture that obtains is adsorbed onto on the silicon-dioxide, and by using the purification by flash chromatography of silica gel, with 3: 1 hexanes: eluent ethyl acetate.Collect required fraction and vacuum concentration, obtain solid, it is dry under high vacuum, obtain 3,5-two bromo-4-brooethyl-methyl benzoate (57) (6.22g, 99%) are yellow solid; LRMS:C
9H
7Br
3O
2(M+Na) m/z=407.MW=386.8669, exact mass=383.7996
Step 2: preparation (3,5-two bromo-4-brooethyl-phenyl)-methyl alcohol (58)
With 0 ℃ 3, (5.2g, 13.44mmol) (30mL 30mmol) handles the solution in tetrahydrofuran (THF) (50mL) 5-two bromo-4-brooethyl-methyl benzoate (57) with the tetrahydrofuran solution of the diisobutylaluminium hydride of 1M.Reaction mixture is stirred 2h at 0 ℃.Still there is raw material in the TLC demonstration.(16mL 16mmol), and stirs 30min with reaction mixture at 0 ℃ at 0 ℃ of tetrahydrofuran solution that adds the diisobutylaluminium hydride of other 1M.To react quencher by reactant being poured on the ice and the mixture of concentrated hydrochloric acid (100mL), and (3 * 150mL) extract with mixture usefulness ethyl acetate.Organic layer is merged, and dried over mgso is filtered, and vacuum concentration, obtains solid, and it is dry under high vacuum, obtains (3,5-dibromo 4-brooethyl-phenyl)-methyl alcohol (58) (4.56g, 94%), is pale solid; LRMS-EI (+): C
8H
7Br
3O (M
+) m/z=356.MW=358.8564, exact mass=355.8047
Step 3: preparation (2,6-two bromo-4-methylol-phenyl)-acetonitrile (59)
Adopt and embodiment 14, the similar method described in the step 5 prepares this compound, and difference is to use (3,5-two bromo-4-brooethyl-phenyl)-methyl alcohol (58) to replace 6-(4-brooethyl-2,6-two chloro-benzyls)-4-sec.-propyl-pyridazin-3-one (54).By using the flash chromatography of silica gel, with 3: 1 to 1: 1 hexanes: the gradient elution of ethyl acetate, with product purification.Collect required fraction and vacuum concentration, obtain solid, it is dry under high vacuum, obtain 2,6-two bromo-4-methylol-phenyl)-acetonitrile (59) (78%), be yellow solid; EI (+)-HRMS m/z:C
9H
7Br
2NO (M
+) calculated value 302.8894, actual measurement 302.8881.MW=304.9702, exact mass=302.8894
Step 4: preparation [2,6-two bromo-4-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-phenyl]-acetonitrile (60)
With 2 under the room temperature, 6-two bromo-4-methylol-phenyl)-and acetonitrile (59) (1.4g, 4.59mmol) solution in methylene dichloride (30mL) is with 3,4-dihydro-2H-pyrans (0.46mL, 5.04mmol) and a hydration tosic acid (16.10mg, 0.085mmol) processing.Reaction mixture is stirred 45min, use saturated sodium bicarbonate aqueous solution (3mL), saturated sodium-chloride water solution (10mL) and water (10mL) to handle then.(3 * 50mL) extract with methylene dichloride with this mixture.Organic layer is merged, and with saturated sodium-chloride water solution (30mL) washing, dried over mgso is filtered and vacuum concentration.By using the flash chromatography (Isco 120g post) of silica gel, with the hexane solution wash-out of 15% ethyl acetate, with the oily matter purifying that obtains.Collect required fraction and vacuum concentration, obtain oily matter, it is dry under high vacuum, obtain [2,6-two bromo-4-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-phenyl]-acetonitrile (60), be faint yellow oily thing (1.52g, 85.4%).Without using with being further purified.Molecular weight=389.0892; Exact mass=386.9470
Step 5: preparation [2,6-two bromo-4-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-phenyl]-acetonitrile (61)
With 25 ℃ [2,6-two bromo-4-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-phenyl]-acetonitrile (60) (1.52g, 3.91mmol) at N, the sodium hydride (192.8mg of the solution in the dinethylformamide (9mL), 4.82mmol, 60% dispersion in mineral oil) handle.Reaction mixture is stirred 10min at 25 ℃.At this moment, will react with 3, and 6-two chloro-4-sec.-propyl-pyridazines (7) (810mg, 4.24mmol) at N, the solution-treated in the dinethylformamide (2mL).Reaction is heated to 90 ℃ then, lasts 1h.At this moment, reaction is cooled to 25 ℃, water (50mL), saturated sodium-chloride water solution (50mL) and saturated sodium bicarbonate aqueous solution (20mL) dilution.This mixture is extracted with ethyl acetate (200mL).Organism is washed with saturated sodium-chloride water solution (100mL), and dried over mgso is filtered, and vacuum concentration.Through Isco chromatogram (120g, silicon-dioxide, 2: 1 hexane/ethyl acetate) obtain (6-chloro-5-sec.-propyl-pyridazine-3-yl)-[2,6-two bromo-4-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-phenyl]-acetonitrile (61) (964mg, 65%), is orange thickness oily matter; C
21H
22Br
2ClN
3O
2(M+H) LRMS is at m/z=542.Molecular weight=543.6894; Exact mass=540.9767
Step 6: preparation 6-(2,6-two bromo-4-chloromethyl-benzyls)-4-sec.-propyl-pyridazin-3-one (62)
With (6-chloro-5-sec.-propyl-pyridazine-3-yl)-[2,6-two bromo-4-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-phenyl]-acetonitrile (61) (332.8mg, 0.61mmol) and sodium acetate (103.8mg, 1.26mmol) mixture heating up in Glacial acetic acid (2.7mL) is to backflow 2.5h.Then backflow 18h is handled and be heated to reactant with concentrated hydrochloric acid (2.0mL).At this moment, reactant is handled with more concentrated hydrochloric acid (6.0mL) and extra Glacial acetic acid (3.0mL), and be heated to backflow, last 24h again.Then reactant is cooled to 25 ℃ and dilute with ethyl acetate (150mL).With this solution with saturated sodium-chloride water solution (2 * 50mL) and saturated aqueous sodium carbonate (1 * 100mL) washs, dried over mgso, filter, and vacuum concentration with the brown oil that obtains with Glacial acetic acid (1.0mL) and concentrated hydrochloric acid (6.0mL) processing, and be heated to backflow 3d.At this moment, reactant is cooled to 25 ℃ and dilute with ethyl acetate (150mL).With this solution with saturated sodium-chloride water solution (2 * 50mL) and saturated aqueous sodium carbonate (1 * 100mL) washing, dried over mgso, filtration, and vacuum concentration.Obtain 6-(2,6-bromo-4-chloromethyl-benzyl)-4-sec.-propyl-pyridazin-3-one (62) (96.3mg, 36%) through flash chromatography (Merck silica gel 60,230-400 order, 2/1 hexane/ethyl acetate), be pale solid; C
15H
15Br
2ClN
2The LRMS of O (M+H) is at m/z=433.Molecular weight=434.5606; Exact mass=431.9240
Step 7: preparation [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetonitrile (63)
With sodium cyanide (279mg, 5.69mmol) suspension in methyl-sulphoxide (2.0mL) is with the vitriol oil (0.10mL), 6-(2,6-two bromo-4-chloromethyl-benzyls)-4-sec.-propyl-pyridazin-3-one (62) (346mg, 0.79mmol) and the other flushing of methyl-sulphoxide (3.0mL) handle.To be reflected at 25 ℃ stirs 5min and stirs 1h at 40 ℃.At this moment, reaction is heated to 60 ℃ of 1h and is cooled to 25 ℃ then.Mixture is poured on the mixture of ice and saturated sodium bicarbonate aqueous solution (50mL).This mixture extraction is arrived ethyl acetate (in 3 * 50mL).With organism saturated sodium-chloride water solution (1 * 50mL) washing, dried over mgso, filtration and the vacuum concentration that merges.Obtain [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetonitrile (63) (227mg, 67%) through flash chromatography (Merck silica gel 60,230-400 order, 1: 2 hexane/ethyl acetate), be the light orange solid; C
16H
15Br
2N
3The LRMS of O (M+H) is at m/z=424.Molecular weight=425.1255; Exact mass=422.9582
Step 8: preparation [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate (64)
(224.2mg, the 0.52mmol) mixture heating up to 135 in concentrated hydrochloric acid (4.0mL) ℃ is lasted 16h with [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetonitrile (63).At this moment, reaction is cooled to 25 ℃ and dilute with saturated sodium-chloride water solution (30mL).This solution is extracted with ethyl acetate (175mL).Organism is washed with saturated sodium-chloride water solution (30mL), and dried over mgso is filtered and vacuum concentration.Obtain the brown solid through ISCO chromatogram (40g post, 9: 1 methylene chloride).This solid is ground with acetonitrile (10mL) and methylene dichloride (2.0mL), filter, and under high vacuum in 110 ℃ of dried overnight, obtain [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate (64) (114.4mg, 48.8%), be pale solid; EI (+)-HRMS m/z:C
16H
16Br
2N
2O
3(M
+) calculated value 240.9964, actual measurement 240.9959.Molecular weight=444.1255; Exact mass=441.9528
Scheme 17: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (69)
Embodiment 16: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene [1,2,4] triazine-6-nitrile (69)
Step 1: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-isoindole-1,3-diketone (65)
With 4-amino-2, and 6-two chloro-phenol (50g, 280.8mmol) and potassium tert.-butoxide (33.16g, 280.8mmol) mixture heating up to 90 in N,N-dimethylacetamide (200mL) ℃.Then with the solution that obtains with 3, (55.31g 280.8mmol) handles 6-two chloro-4-sec.-propyl-pyridazines.To be reflected at 90 ℃ of heating 17h.At this moment, will react with methyl tertiary butyl ether (700mL) and saturated sodium-chloride water solution (800mL) dilution.Organic layer is separated, and water (2 * 400mL) washs and is concentrated to～volume of 200mL.With this solution with toluene (800mL) dilution then distillation remove～solvent of 300mL.With rest solution be cooled to 80 ℃ and with Tetra hydro Phthalic anhydride (42.01g 280.8mmol) handles.This mixture heating up is arrived backflow 4h, simultaneously with the water component distillation.At this moment, reaction is concentrated in vacuo to～200mL,, concentrates then to remove～solvent of 300mL with Glacial acetic acid (800mL) dilution.(46.06g 561.6mmol) handles, and is heated to backflow 6h will to react the usefulness sodium acetate.At this moment, with reactant cool to room temperature and water (500mL) dilution.This mixture is warming to 60 ℃, stirs 30min cool to room temperature then.The solid by filtration that obtains is collected, use Glacial acetic acid: 1: 1 mixture (300mL) washing of water, then water (150mL) washing, (under house vacuum) drying under indoor vacuum, then in vacuum oven in 55 ℃ of dried overnight, obtain 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-isoindole-1,3-diketone (84.8g, 68%), is pale solid; C
21H
15Cl
2N
3O
4(M+H)
+ES (+)-LRMS at m/z=444.Exact mass=443.0440; Molecular weight=444.28.
Step 2: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-isoindole-1,3-diketone (66)
With 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-isoindole-1,3-diketone (65) (84.5g, 190.2mmol) at N, the suspension in the dinethylformamide dimethyl-acetal (250mL) is heated to backflow 5h.At this moment, will react cool to room temperature.The solid by filtration that obtains is collected, use methyl tertiary butyl ether: 1: 1 mixture (70mL) washing of heptane, then with heptane (70mL) washing, and vacuum-drying obtains 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-isoindole-1,3-diketone (66) (63.57g, 73%) is pale solid; C
22H
17Cl
2N
3O
4(M+H)
+ES (+)-LRMS at m/z=458.Exact mass=457.0596; Molecular weight=458.30.
Step 3: preparation 6-(4-amino-2,6-two chloro-phenoxy groups)-4-sec.-propyl-2-methyl-2H-pyridazin-3-one (67)
With 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-isoindole-1,3-diketone (66) (64g, 139.6mmol) (34.67mL 349mmol) handles with butylamine for mixture in methyl alcohol (500mL).Mixture heating up is arrived backflow 1.5h.At this moment, will react cool to room temperature and drip water (384mL) and handle.The solid by filtration that obtains is collected, with 1: 1 solution (180mL) of methanol, then water (250mL) washing, and vacuum-drying, obtain 6-(4-amino-2,6-two chloro-phenoxy groups)-4-sec.-propyl-2-methyl-2H-pyridazin-3-one (67) (34.12g, 74.4%), is pale solid; C
14H
15Cl
2N
3O
2(M+H)
+ES (+)-LRMS at m/z=328.Exact mass=327.0541; Molecular weight=328.20.
Step 4: preparation (2-cyano group-2-([3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-hydrazono-}-ethanoyl)-urethanum (68)
With 6-(the 4-amino-2 that is cooled to 5-10 ℃, 6-two chloro-phenoxy groups)-4-sec.-propyl-2-methyl-2H-pyridazin-3-one (67) (10g, 30.47mmol) (2.3g, 32.3mmol) solution in water (6mL) is dropwise handled with Sodium Nitrite for mixture in Glacial acetic acid (60mL) and concentrated hydrochloric acid (9.06mL).Reactant is stirred 30min at 5-10 ℃.At this moment, (5.34g 33.52mmol) handles, then with sodium acetate (7.5g, 91.41mmol) solution-treated in water (22.5mL) with N-cyano group acetylamino ethyl formate with reactant.Reactant is stirred 30min at 5-10 ℃, water (50mL) dilution then.The solid by filtration that obtains is collected, use Glacial acetic acid: 1: 1 mixture (40mL) of water, then water (2 * 60mL) washings, dry under indoor vacuum, then 50 ℃ of vacuum-dryings, obtain (2-cyano group-2-{[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-hydrazono-}-ethanoyl)-urethanum (68) (15.04g, 95%), is orange solids; C
20H
20Cl
2N
6O
5(M+H)
+ES (+)-LRMS at m/z=495.Exact mass=494.0872; Molecular weight=495.33.
Step 5: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (69)
With (2-cyano group-2-{[3; 5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1; 6-dihydro-pyridazine-3-base oxygen base)-phenyl]-hydrazono-}-ethanoyl)-urethanum (68) (6.5g; 13.12mmol) and potassium acetate (1.42g; 14.43mmol) at N; solution in the N-N,N-DIMETHYLACETAMIDE is heated to 120 ℃, lasts 2h.At this moment, handle with the reactant cool to room temperature and with Glacial acetic acid (1.5mL) and water (65mL).With mixture at stirring at room 15min.The solid by filtration that obtains is collected, and water (65mL) washing, and vacuum-drying obtain orange solids.Solid suspension in acetonitrile (36mL), is heated to backflow 3h cool to room temperature then.Then the solid by filtration that obtains is collected,, obtain 2-[3 with acetonitrile (12mL) and methyl tertiary butyl ether (24mL) washing and vacuum-drying, 5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-and phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene [1,2,4] triazine-6-nitrile (69) (5.06g, 85.8%), is orange solids; ES (+)-HRMS m/e:C
18H
14Cl
2N
6O
4(M+H)
+Calculated value 449.0527, actual measurement 449.0527.Exact mass=448.0454; Molecular weight=449.26.
Scheme 18: synthetic [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-acetate (76)
Embodiment 17: synthetic [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-acetate (76)
Step 1: preparation 4-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-2,6-two chloro-phenol (70)
With 25 ℃ 2,6-two chloro-4-(2-hydroxyl-ethyl)-phenol (16) (2.0g, 9.66mmol) solution in methylene dichloride (20mL) with triethylamine (1.35mL, 9.66mmol) and the t-butyldiphenylsilyl muriate (2.48mL 9.66mmol) handles.Reactant is stirred 18h at 25 ℃.At this moment, with methylene dichloride diluting reaction thing.Organism is washed with 1N aqueous hydrochloric acid, water and saturated sodium-chloride water solution, and dried over mgso is filtered and vacuum concentration.Obtain 4-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl through flash chromatography (Merck silica gel 60,230-400 order, 95: 5 petrol ether/ethyl acetate)]-2,6-two chloro-phenol (70) (2.60g, 60%) are faint yellow oily thing; HRMS m/e:C
24H
26Cl
2O
2Si (M+Na)
+Calculated value 467.0971, actual measurement 467.0977.Exact mass=444.1079; Molecular weight=445.47.
Step 2: preparation dimethyl-thiocarbamate O-{4-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-2,6-two chloro-phenyl } ester (71)
With 25 ℃ 4-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-2,6-two chloro-phenol (70) (289mg, 0.78mmol) at N, solution in the dinethylformamide (4mL) is with 1,4-diazabicyclo [2.2.2] octane (172 μ L, 1.56mol) and dimethyl sulphide (154mg 1.25mmol) handles for urea chloride.Reactant is stirred 18h at 25 ℃.At this moment, reactant is diluted with ethyl acetate, with 1N aqueous hydrochloric acid, water and saturated sodium-chloride water solution washing, dried over mgso is filtered and vacuum concentration then.Through flash chromatography (Merck silica gel 60,230-400 order, 95: 5 petrol ether/ethyl acetate) obtain dimethyl-thiocarbamate O-{4-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-2,6-two chloro-phenyl } ester (71) (376mg, 90%), is white solid; EI (+)-HRMS m/e:C
27H
31Cl
2N
2O
2SSi (M+H)
+Calculated value 532.1295, actual measurement 532.1292.Exact mass=531.1222; Molecular weight=532.61
Step 3: preparation dimethyl-thiocarbamate S-{4-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-2,6-two chloro-phenyl } ester (72)
With dimethyl-thiocarbamate O-{4-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-2,6-two chloro-phenyl } (2.98g 5.60mmol) is heated to 190-200 ℃ to ester (71), lasts 24h.At this moment, resistates is cooled to 25 ℃ and be dissolved in the methylene dichloride.Through flash chromatography (Merck silica gel 60,230-400 order, 95/5 petrol ether/ethyl acetate) obtain dimethyl-thiocarbamate S-{4-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-2,6-two chloro-phenyl } ester (72) (2.08g, 70%), is the oily matter of light color; EI (+)-HRMS m/e:C
27H
31Cl
2NO
2SSi (M+H)
+Calculated value 532.1295, actual measurement 532.1301.Exact mass=531.1222; Molecular weight=532.61
Step 4: preparation 2-(3,5-two chloro-4-sulfydryl-phenyl)-ethanol (73)
With dimethyl-thiocarbamate S-{4-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-2,6-two chloro-phenyl } ester (72) (2.0g, 3.76mmol) (4.4mL 13.2mmol) handles with the 3N potassium hydroxide aqueous solution for solution in ethanol (6.0mL).Reactant is heated to 95 ℃ then, lasts 18h.At this moment, reactant is poured on the water (200mL), is acidified to pH=2, be extracted into methylene dichloride then (in 3 * 100mL) with the 3N aqueous hydrochloric acid.With the organism water (1 * 100mL) and saturated sodium-chloride water solution (1 * 100mL) washing, dried over mgso is filtered, and vacuum concentration.Obtain 2-(3,5-two chloro-4-sulfydryl-phenyl)-ethanol (73) (639mg, 76%) through flash chromatography (Merck silica gel 60,230-400 order, 80: 20 petrol ether/ethyl acetate), be white solid; EI (+)-HRMS m/e:C
8H
8Cl
2OS (M
+) calculated value 221.9673, actual measurement 221.9672.Exact mass=221.9673; Molecular weight=223.12
Step 5: preparation 2-[3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base sulfenyl)-phenyl]-ethanol (74)
With 2-(3,5-two chloro-4-sulfydryl-phenyl)-ethanol (73) (620mg, 2.78mmol) solution in methyl-sulphoxide (25mL) is with 3,6-two chloro-4-sec.-propyl-pyridazines (7) (530mg, 2.78mmol) and salt of wormwood (1.54g, 11.12) handle.With the mixture heating up to 90 that obtains ℃, last 18h.At this moment, reactant is cooled to 25 ℃, is poured on the solution of water (200mL) and 1N aqueous hydrochloric acid (25mL).(2 * 200mL) extract with ethyl acetate with mixture.Then with the organism water (1 * 100mL) and saturated sodium-chloride water solution (1 * 100mL) washing, dried over mgso is filtered, and vacuum concentration.Obtain 2-[3 through flash chromatography (Merck silica gel 60,230-400 order, 70: 30 petrol ether/ethyl acetate), 5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base sulfenyl)-phenyl]-ethanol (74) (550mg, 52%), be light yellow oil; EI (+)-HRMS m/e:C
15H
15Cl
3N
2OS (M+H)
+Calculated value 377.0044, actual measurement 377.0043.Exact mass=375.9971; Molecular weight=377.72
Step 6: preparation [3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base sulfenyl)-phenyl]-acetate (75)
With the 2-[3 that is cooled to 0 ℃, 5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base sulfenyl)-phenyl]-ethanol (74) (100mg, 0.26mmol) Jones reagent solution (0.21mL, 0.57mmol is via the standard method preparation) processing of 2.7M of the solution in acetone (2.0mL).Reactant is stirred 1.25h at 0 ℃.At this moment, reactant is handled with the 2-propyl alcohol, become green until red solution.Then, this mixture is diluted with ethyl acetate (50mL) and water (25mL).With separating organic matters, use dried over mgso, filter, and vacuum concentration, obtain [3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base sulfenyl)-phenyl]-acetate (75) (92.5mg, 89%), be the canescence foam.With this material without using with being further purified; C
15H
13Cl
3N
2O
2S (M+H)
+LRMS-APCI at m/z=390.Exact mass=389.9763; Molecular weight=391.71
Step 7: preparation [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-acetate (76)
Will [3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base sulfenyl)-phenyl]-acetate (75) (90mg, 0.23mmol) and sodium acetate (66mg, the 0.80mmol) mixture heating up to 100 in Glacial acetic acid (2.5mL) ℃ is lasted 7h.At this moment, with the reactant vacuum concentration.With resistates at methylene dichloride: form slurries three times in 1: 1 solution of hexane, then vacuum concentration.With solid water (100mL) dilution that obtains, handle so that pH regulator is arrived 10-11 with the 1N aqueous sodium hydroxide solution then.With this solution ethyl acetate extraction.Abandon organism.With the 1N aqueous hydrochloric acid water layer is acidified to pH=2-3 then.(2 * 100mL) extract with ethyl acetate with this solution then.(1 * 100mL) washing, dried over mgso is filtered, and vacuum concentration with saturated sodium-chloride water solution with organism.Obtain [3 through flash chromatography (Merck silica gel 60,230-400 order contain 70: 30 hexane/ethyl acetate of 2% Glacial acetic acid), 5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-acetate (76) (41mg, 17.5%), be white solid; EI (+)-HRMS m/e:C
15H
14Cl
2N
2O
3S (M+H)
+Calculated value 373.0175, actual measurement 373.0175.Exact mass=372.0102; Molecular weight=373.26
Scheme 19: synthetic [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-sulfinyl)-phenyl]-acetate (77) and [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-acetate (78)
Embodiment 18: synthetic [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-sulfinyl)-phenyl]-acetate (78)
With
Embodiment 19: synthetic [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-acetate (79)
Step 1: preparation [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-sulfinyl)-phenyl]-acetate (77) and [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-acetate (78)
(75mg, 0.2mmol) mixture in formic acid (1.0mL) is with 30% aqueous hydrogen peroxide solution (61 μ L, 0.6mmol) processing with [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-acetate (76) of 0 ℃.The suspension that obtains is stirred 30min at 0 ℃, stir 7d at 25 ℃ then, during this period, in reactant, add more 30% aqueous hydrogen peroxide solution (amounting to 322 μ L), formic acid (1.0mL) and ethanol (1.0mL).At this moment, reactant is poured on ethyl acetate/waterborne and with ethyl acetate (2 * 50mL) extractions.With the organism dried over mgso, filter and vacuum concentration.Obtain [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-sulfinyl)-phenyl]-acetate (77) (32mg, 41%) through HPLC (the 20-70 acetonitrile/water that contains 0.1% trifluoroacetic acid is in 30min), be white solid.ES-HRMS m/e:C
15H
14Cl
2N
2O
4S (M+H)
+Calculated value 389.0124, actual measurement 389.0124: exact mass=388.0051; Molecular weight=389.26; [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-acetate (78) (22mg, 27%) is white solid; EI (+)-HRMS m/e:C
15H
14Cl
2N
2O
5S (M+H)
+Calculated value 377.0044, actual measurement 377.0043: exact mass=404.0000; Molecular weight=405.26
Scheme 20: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (88)
Embodiment 20: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (88)
Step 1: preparation dimethyl-thiocarbamate O-(2,6-two chloro-4-nitro-phenyl) ester (79)
With 25 ℃ 2, (3.0g is 14.4mmol) at N for 6-two chloro-4-nitro-phenol, solution in the dinethylformamide (70mL) is with 1, (3.16mL, 28.8mmol) (2.85g 23.04mmol) handles 4-diazabicyclo [2.2.2] octane for urea chloride with dimethyl sulphide.Reactant is stirred 18h at 25 ℃.At this moment, with reactant with ethyl acetate (250mL) dilution, use then the 1N aqueous hydrochloric acid (1 * 125mL), water (1 * 125mL) and saturated sodium-chloride water solution (1 * 125mL) washing, dried over mgso, the filtration and vacuum concentration.Obtain dimethyl-thiocarbamate O-(2,6-two chloro-4-nitro-phenyl) ester (79) (3.2g, 75%) through flash chromatography (Merck silica gel 60,230-400 order, 80: 20 petrol ether/ethyl acetate), be white solid; C
9H
8Cl
2N
2O
3S (M-Cl)
+EI-LRMS at m/z=259.Exact mass=293.9633; Molecular weight=295.15
Step 2: preparation dimethyl-thiocarbamate S-(2,6-two chloro-4-nitro-phenyl) ester (80)
(3.2g 10.8mmol) is heated to 180 ℃ to ester (79) with dimethyl-thiocarbamate O-(2,6-two chloro-4-nitro-phenyl), last 20min, obtain dimethyl-thiocarbamate S-(2,6-two chloro-4-nitro-phenyl) ester (80) (3.23g), for brown solid-state.With this material without using with being further purified; C
9H
8Cl
2N
2O
3S (M+H)
+EI-LRMS at m/z=295.Exact mass=293.9633; Molecular weight=295.15
Step 3: preparation dimethyl-thiocarbamate S-(4-amino-2,6-two chloro-phenyl) ester (81)
With dimethyl-thiocarbamate S-(2,6-two chloro-4-nitro-phenyl) ester (80) (1.6g, the 5.4mmol) iron powder of the mixture in Glacial acetic acid (24mL), 2-propyl alcohol (48mL) and water (24mL) (2.1g, 37.8mmol) processing that is heated to 50 ℃.With the mixture heating up to 95 that obtains ℃, last 2h.At this moment, reactant is passed through C salt pad heat filtering, and water and ethyl acetate washing.Filtrate is concentrated to remove most organism.With rest solution water (500mL) dilution, be adjusted to pH=8 with ammonium hydroxide solution,stronger then.(3 * 200mL) extract this solution with ethyl acetate.With the organism dried over mgso that merges, filter and vacuum concentration.The resistates that obtains is formed slurries with ether, and in water cooler, cool off 30min.The solid by filtration that forms is collected and washed with cold diethyl ether, obtain dimethyl-thiocarbamate S-(4-amino-2,6-two chloro-phenyl) ester (81) (1.33g, 93%), be white solid; EI (+)-HRMS m/e:C
9H
10Cl
2N
2OS (M+H)
+Calculated value 264.9964, actual measurement 264.9964.Exact mass=263.9891; Molecular weight=265.16
Step 4: preparation 4-amino-2,6-two chloro-benzenethiols (82)
(2.0g, ethanolic soln 7.5mmol) is handled with the 3N potassium hydroxide aqueous solution with dimethyl-thiocarbamate S-(4-amino-2,6-two chloro-phenyl) ester (81).Reactant is heated to 95 ℃, lasts 2d.At this moment, reactant is cooled to 25 ℃, is acidified to pH=2 with the 3N aqueous hydrochloric acid then.With this solution with water (500mL) dilution, use ethyl acetate (2 * 250mL) extractions then.With the organism dried over mgso, filter, and vacuum concentration, obtain orange solids.This solid is formed slurries in chloroform, collect and wash with chloroform by filtering.With the filtrate vacuum concentration and by flash chromatography (Merck silica gel 60,230-400 order, 85: 15 petrol ether/ethyl acetate) purifying, obtain 4-amino-2,6-two chloro-benzenethiols (82) (1.0g, 69%) are white solid; EI (+)-HRMS m/e:C
6H
5Cl
2NS (M
+) calculated value 192.9520, actual measurement 192.9519.Exact mass=192.9520; Molecular weight=194.08
Step 5: preparation 3,5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base sulfenyl)-aniline (83)
With 25 ℃ 4-amino-2,6-two chloro-benzenethiols (82) (1.0g, 5.2mmol) at N, the solution in the dinethylformamide is with 3,6-two chloro-4-sec.-propyl-pyridazines (7) (990mg, 5.2mmol) and salt of wormwood (2.16g 15.6mmol) handles.With the mixture heating up to 90 that obtains ℃, last 18h.At this moment, reactant is cooled to 25 ℃, is poured on the mixture (10mL) of frozen water and 1N aqueous hydrochloric acid.With other 1N aqueous hydrochloric acid the solution that obtains is adjusted to pH=7, uses ethyl acetate (2 * 100mL) extractions then.(1 * 50mL) washing, dried over mgso is filtered and vacuum concentration with saturated sodium-chloride water solution with organism.Obtain 3 through flash chromatography (Merck silica gel 60,230-400 order, 80/20 petrol ether/ethyl acetate), 5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base sulfenyl)-aniline (83) (1.29g, 72%) are the canescence foam; ES (+)-HRMS m/e:C
13H
12Cl
3N
3S (M+H)
+Calculated value 347.9891, actual measurement 347.9889.Exact mass=346.9817; Molecular weight=348.68
Step 6: preparation N-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-ethanamide (84)
With 3, (1.23g, 3.50mmol) (1.0g 12.25mmol) handles the solution in Glacial acetic acid (35mL) 5-two chloro-4-(6-chloro-5-sec.-propyl-pyridazine-3-base sulfenyl)-aniline (83) with sodium acetate.With this mixture heating up to 95 ℃, last 18h.At this moment, reaction mixture is cooled to 25 ℃, is poured on water (200mL) and upward and with the 3N aqueous sodium hydroxide solution neutralizes.(2 * 200mL) extract with ethyl acetate with this solution then.With organism saturated sodium-chloride water solution (1 * 100mL) washing that merges, dried over mgso, filter and vacuum concentration, obtain N-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-ethanamide (84) (1.3g, 99%), be pale solid.With this material without using with being further purified; ES (+)-HRMS m/e:C
15H
15Cl
2N
3O
2S (M+H)
+Calculated value 372.0335, actual measurement 372.0335.Exact mass=371.0262; Molecular weight=372.28
Step 7: preparation 6-(4-amino-2,6-two chloro-thiophenyls)-4-sec.-propyl-2H-pyridazin-3-one (85)
With N-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-(4.0g, 10.7mmol) (2.14g 53.5mmol) handles the mixture in methyl alcohol (15mL) and water (15mL) ethanamide (84) with powdered sodium hydroxide.Then reactant is heated to backflow 18h.At this moment, reaction is cooled to 25 ℃, water (500mL) dilutes and (3 * 300mL) extract with ethyl acetate.(1 * 200mL) washing, dried over mgso is filtered and vacuum concentration, obtains 6-(4-amino-2,6-two chloro-thiophenyls)-4-sec.-propyl-2H-pyridazin-3-one (85) (3.5g, 99%), is light brown brown solid with saturated sodium-chloride water solution with organism.With this material without using with being further purified; ES (+)-HRMSm/e:C
13H
13Cl
2N
3OS (M+H)
+Calculated value 330.0229, actual measurement 330.0229.Exact mass=329.0156; Molecular weight=330.24
Step 8: preparation (2-cyano group-2-{[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-hydrazono-}-ethanoyl)-urethanum (86)
With 6-(the 4-amino-2 that is cooled to 0 ℃, 6-two chloro-thiophenyls)-4-sec.-propyl-2H-pyridazin-3-one (85) (3.40g, 10.4mmol) (853mg, 12.36mmol) solution in water (7.0mL) is by handling under pasteur pipet, the surface at reaction mixture with Sodium Nitrite for mixture in water (135mL) and concentrated hydrochloric acid (68mL).Carry out the water flushing (1.0mL) of pasteur pipet after this.The yellow mixture that obtains is stirred 30min at 0 ℃.Add more concentrated hydrochloric acid (7.0mL).With reactant at 0 ℃ of restir 1.3h.Remove solid by filter paper filtering, and the water flushing.With the diazonium salt solution of clarifying yellow filtrate be poured on fast the cyano group acetylamino ethyl formate that is cooled to 0 ℃ (1.77g, 11.33mmol), on the solution of pyridine (75mL) and water (204mL).After the mixing, form orange red solid immediately.This mixture is stirred 1h at 0 ℃.At this moment, collect solid by filter paper filtering.Solid is washed with water, dry air 2h under indoor vacuum, vacuum-drying then, obtain (2-cyano group-2-{[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-hydrazono-}-ethanoyl)-urethanum (86) (2.98g, 58%), be orange solids; ES (+)-HRMS m/e:C
19H
18Cl
2N
6O
4S (M+H)
+Calculated value 497.0560, actual measurement 497.0559.Exact mass=496.0487; Molecular weight=497.36
Step 9: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (87)
With (2-cyano group-2-{[3; 5-two chloro-4-(5-sec.-propyl-6-oxo-1; 6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-hydrazono-}-ethanoyl)-(2.98g, 5.99mmol) (2.46g 29.95mmol) handles the solution in Glacial acetic acid (60mL) urethanum (86) with sodium acetate.With the mixture heating up to 120 that obtains ℃, last 3h.At this moment, LCMS shows the raw material completely consumed and changes into product.Reactant is cooled to 25 ℃, and upward and with ethyl acetate (2 * 150mL) extract to be poured on water (200mL).(1 * 150mL) washing, dried over mgso is filtered and vacuum concentration, obtains orange solids with saturated sodium-chloride water solution with organism.This solid is dissolved in 1: 1 methylene dichloride: in the hexanes mixtures and vacuum concentration three times.Then it is dissolved in 1: 1 methylene dichloride: in the carbinol mixture and vacuum concentration, obtain 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (87) (2.79g) is orange solids.With this material without using with being further purified; ES (+)-HRMS m/e:C
17H
12Cl
2N
6O
3S (M+H)
+Calculated value 451.0142, actual measurement 451.0143.Exact mass=450.0069; Molecular weight=451.29
Step 10: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (88)
With 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-and phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (87) (45mg, 0.09mmol) (0.28mL 0.98mmol) handles with 30% aqueous hydrogen peroxide solution for mixture in Glacial acetic acid (2.5mL).Reactant is heated to 80 ℃, lasts 3d.Add every day additional quantity 30% aqueous hydrogen peroxide solution (0.28mL, 0.98mmol).Behind the 3d, reactant is diluted with ethyl acetate and water.Organism is washed with water, and dried over mgso is filtered and vacuum concentration.Through HPLC (the 20-70 acetonitrile/water that contains 0.1% trifluoroacetic acid, in 30min) obtain 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (88) (2.0mg, 4%) is white solid; ES (+)-HRMS m/e:C
17H
12Cl
2N
6O
5S (M+H)
+Calculated value 483.9940, actual measurement 483.0041.Exact mass=481.9967; Molecular weight=483.29
Scheme 21: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-2H-[1,2,4] triazine-3,5-diketone (91)
Embodiment 21: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-2H-[1,2,4] triazine-3,5-diketone (91)
Step 1: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-carboxylic acid (89)
With 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-and phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (87) (1.35g, 2.99mmol) solution in Glacial acetic acid (30mL) and concentrated hydrochloric acid (6.7mL) is heated to 120 ℃, lasts 3d.At this moment, reactant is cooled to 0 ℃, water (50mL) dilutes and stirs 15min at 0 ℃.Sedimentary product is collected water and petroleum ether, dry air 15min under indoor vacuum by filtering, vacuum-drying then obtains 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-and phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-carboxylic acid (89) (1.17g, 83%), is the light brown solid; ES (+)-HRMS m/e:C
17H
13Cl
2N
5O
5S (M+H)
+Calculated value 470.0087, actual measurement 470.0088.Exact mass=469.0014; Molecular weight=470.29
Step 2: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-2H-[1,2,4] triazine-3,5-diketone (90)
With 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-and phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-carboxylic acid (89) (1.0g, 2.13mmol) and Thiovanic acid (21.3mL, mixture 2.13mmol) 170 ℃ the heating 3.5h.At this moment, reactant is cooled to 25 ℃ and water (500mL) dilution.By adding saturated sodium bicarbonate aqueous solution water layer is adjusted to pH=4.Precipitated solid is collected water, sherwood oil, pH=5 damping fluid and water continuous washing by filtering.With solid dry air 15min under indoor vacuum, vacuum-drying then obtains the light brown solid.This solid is dissolved in the 1N aqueous sodium hydroxide solution (100mL) and with ethyl acetate (1 * 120mL) extraction.By adding 1N aqueous hydrochloric acid (15mL) water layer is neutralized.The solid by filtration that obtains is collected, water (200mL) and sherwood oil (100mL) washing, dry air vacuum-drying then obtains 2-[3 under indoor vacuum, 5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-2H-[1,2,4] triazine-3,5-diketone (90) (338mg, 37%), is the brown solid; ES (+)-HRMS m/e:C
16H
13Cl
2N
5O
3S (M+H)
+Calculated value 426.0189, actual measurement 426.0189.Exact mass=425.0116; Molecular weight=426.28
Step 3: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-2H-[1,2,4] triazine-3,5-diketone (91)
With 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-2H-[1,2,4] triazine-3,5-diketone (90) (165mg, 0.38mmol) (0.93mL 3.87mmol) handles with 30% aqueous hydrogen peroxide solution for mixture in Glacial acetic acid (10mL).Reaction mixture is heated to 90 ℃ then, lasts 3d.At this moment, reactant is cooled to 25 ℃ and be poured on the water (100mL).(1 * 125mL) extracts with ethyl acetate with this solution.Organism is washed with water, and dried over mgso is filtered and vacuum concentration.Through HPLC (condition: the 20-80-30 acetonitrile/water that contains 0.1% trifluoroacetic acid, in 30min) obtain 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-2H-[1,2,4] triazine-3,5-diketone (91) (48.5mg, 27%), is white solid; ES (+)-HRMS m/e:C
16H
13Cl
2N
5O
5S (M+H)
+Calculated value 458.0087, actual measurement 458.0090.Exact mass=457.0014; Molecular weight=458.28
Scheme 22: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (96)
Embodiment 22: Synthetic 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (96)
Step 1: preparation [2,6-two chloro-4-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-phenyl]-acetonitrile (92)
(910mg, 2.90mmol) (430mg 2.9mmol) handles the solution in Glacial acetic acid (12mL) with Tetra hydro Phthalic anhydride with 6-(4-amino-2,6-two chloro-benzyls)-4-sec.-propyl-2H-pyridazin-3-one.Reactant is heated to 130 ℃ then, lasts 3.5h.At this moment, reactant being poured on water (200mL) goes up and is extracted in the ethyl acetate (300mL).Then organism is washed with water, dried over mgso is filtered and vacuum concentration.The orange solids that obtains is formed slurries in cold acetonitrile, collect by filtering, with cold acetonitrile washing and vacuum-drying, obtain 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-isoindole-1,3-diketone (92) (780mg, 61%), is light brown brown solid; C
22H
17Cl
2N
3O
3(M+H)
+ES (+)-LRMS at m/z=442.Exact mass=441.0647; Molecular weight=442.3051
Step 2: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-isoindole-1,3-diketone (93)
With 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-isoindole-1,3-diketone (92) (570mg, 1.29mmol) and N, the mixture heating up to 105 of dinethylformamide dimethyl-acetal (12mL) ℃ is lasted 4.5h.At this moment, reactant is cooled to 25 ℃ and dilute with methylene dichloride.With this solution with water (1 * 50mL) and saturated sodium-chloride water solution (1 * 50mL) washing, dried over mgso is filtered and vacuum concentration.Obtain 2-[3 through flash chromatography (Merck silica gel 60,230-400 order, 95: 5 methylene chloride), 5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-isoindole-1,3-diketone (93) (310mg, 52%), is pale solid; ES-HRMS m/e:C
23H
19Cl
2N
3O
3(M+H)
+Calculated value 456.0876, actual measurement 456.0876.Exact mass=455.0803; Molecular weight=456.3322.
Step 3: preparation 6-(4-amino-2,6-two chloro-benzyls)-4-sec.-propyl-2-methyl-2H-pyridazin-3-one (94)
With 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-isoindole-1, (300mg, 0.66mmol) solution in Glacial acetic acid is heated to 110 ℃ to 3-diketone (93), lasts 3h.At this moment, reactant is cooled to 25 ℃ and be poured on the water (100mL).(3 * 50mL) extract with ethyl acetate with this mixture.Organism is washed with saturated sodium-chloride water solution, and dried over mgso is filtered and vacuum concentration, obtains brown oil.Recrystallization from ether and hexane is then by flash chromatography (Merck silica gel 60,230-400 order, 30: 70 ethyl acetate/petroleum ether), obtain 6-(4-amino-2,6-two chloro-benzyls)-4-sec.-propyl-2-methyl-2H-pyridazin-3-one (94) (148mg, 69%), is pale solid; ES-HRMS m/e:C
15H
17Cl
2N
3O (M+H)
+Calculated value 326.0822, actual measurement 326.0822.Exact mass=325.0749; Molecular weight=326.2282.
Step 4: preparation (2-cyano group-2-{[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-hydrazono-}-ethanoyl)-urethanum (95)
With 6-(the 4-amino-2 that is cooled to 0 ℃, 6-two chloro-benzyls)-4-sec.-propyl-2-methyl-2H-pyridazin-3-one (94) (148mg, 0.45mmol) (37.3mg, 0.54mmol) solution in water (0.5mL) is via handling under the surface of pasteur pipet at reaction mixture with Sodium Nitrite for mixture in water (6mL) and concentrated hydrochloric acid (3mL).Carry out the water flushing (0.5mL) of pasteur pipet after this.The pale yellow solution that obtains is stirred 45min at 0 ℃.At this moment, with reactant filter and directly be discharged to by the cotton pad cyano group acetylamino ethyl formate that is cooled to 0 ℃ (77.3mg, 0.49mmol), in the solution of pyridine (3mL) and water (9mL).After mixing, form orange red solid immediately.This mixture is stirred 30min at 0 ℃.At this moment, collect solid by filter paper filtering.With solid water and petroleum ether, dry air under indoor vacuum, vacuum-drying then, obtain (2-cyano group-2-{[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-hydrazono-}-ethanoyl)-urethanum (95) (192mg, 86%), be orange solids; ES-HRMSm/e:C
21H
22Cl
2N
6O
4(M+H)
+Calculated value 493.1153, actual measurement 493.1155.Exact mass=492.1080; Molecular weight=493.3533.
Step 5: preparation 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (96)
With (2-cyano group-2-{[3; 5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1; 6-dihydro-pyridazine-3-ylmethyl)-phenyl]-hydrazono-}-ethanoyl)-urethanum (95) (190mg; 0.38mmol) (158mg 1.15mmol) handles with sodium acetate for solution in Glacial acetic acid (4mL).With the mixture heating up to 120 that obtains ℃, last 3.5h.Reactant is cooled to 25 ℃, is poured on then on the water (125mL).The orange mixture that obtains is extracted with ethyl acetate (150mL).The organism that merges is washed with saturated sodium-chloride water solution, and dried over mgso is handled with the neutral decolorizing charcoal of Norite, filters and washs with ethyl acetate by C salt.With the filtrate vacuum concentration.Purifying through HPLC (the 10-90 acetonitrile/water that contains 0.1% trifluoroacetic acid is in 30min) obtains 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-and phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile (96) (87.2mg, 44%), is pale solid; ES-HRMS m/e:C
19H
16Cl
2N
6O
3(M+H)
+Calculated value 447.0734, actual measurement 447.0735.Exact mass=446.0661; Molecular weight=447.2838.
Embodiment 23:TR/RXR/GRIP test
In this embodiment, adopt TR/RXR/GRIP to test and test representational formula (I) compound.The abbreviation of using: H6-TR β has the ligand binding domains of the Thyroid Hormone Receptors β of six His marks; .H6-TR α. have the ligand binding domains of the Thyroid Hormone Receptors α of six His marks; EE-RxR α, have the EE-mark the ligand binding domains of retinoid X receptor; APC, allophycocyanin; BSA, bovine serum albumin; DMSO, methyl-sulphoxide.
Material
The ligand binding domains (amino acid/11 48-410) (H6-TR β) of Thyroid Hormone Receptors β and the ligand binding domains (amino acid 202-461) (H6-TR α) of Thyroid Hormone Receptors α are cloned into E.coli expression vector pET28a (Novagen, Milwaukee, WI) in, this carrier contains six His sequences of N-end.The albumen of the reorganization six His marks that obtain is produced in E.coli BL21 (DE3) cell.With cell at Terrific Broth (personal self-control Bacto Tryptones (3.3%, w/v), the Difico yeast extract (2.0%, w/v) and NaCl (0.5%, substratum w/v)) in the growth, bottle is shaken in use, in 0.2mM IPTG in 25 ℃ of incubations 24 hours, results or with buffer A (0.05M Tris, the 0.3M NaCL of 5 volumes, the 1%W/V trimethyl-glycine, 0.01M imidazoles, 0.02M b-mercaptoethanol, pH 8.0) dissolving.(1.0mg/ml Sigma) and CompleteProtease Inhibitor Cocktail (Roche Diagnostics Gmbh), and with ultrasonic one minute of solution, carries out 5 times at 4 ℃ to add N,O-Diacetylmuramidase in slurries.With suspension in Ti45 Beckman rotor centrifugal 2 hours, and supernatant liquor installed on NI NTAAgarose (Quigen 30210) post with 127,300 RCF.After with the buffer A washing, H6-TR β or H6-TR α are contained the buffer A wash-out of 0.25M imidazoles.
The ligand binding domains of the X acceptor of people's retinoid (amino acid 225-462) (RxR α) is designed to have terminal His6 of N-and EE (EFMPME) mark, the zymoplasm resolvation site between His6 and EE sequence, and be cloned into the pACYC carrier.The albumen of the His6-EE-mark that obtains is produced in the E.coli cell.Bottle is shaken in use, in 0.1mM IPTG under 18 hours condition of 18 ℃ of incubations grown cell, with cell harvesting and with the buffer B of 5 volumes (0.025M Tris, 0.3M NaCl, 0.02 M imidazoles, the 0.01M beta-mercaptoethanol pH8.0) suspends.(0.2mg/ml Sigma) stirs 30min with Complete Protease Inhibitor Cocktail (Roche DiagnosticsGmbh) and at 4 ℃ to add N,O-Diacetylmuramidase.With suspension 4 ℃ ultrasonic 30 seconds, 5 times.With suspension at the centrifugal 20min of 12,000 RCF.With membrane filtration and the adding 0.5%NP-40 of supernatant liquor with 0.45 μ m aperture.With the protein binding of His6-mark in NiNTA metal-affinity resin (QIAGEN, Valencia, CA) and therefrom wash-out.Albumen is concentrated and dialysis.
Remove the His6 mark by zymoplasm digestion from EE-RxR α, every mg albumen uses the zymoplasm (Pharmacia (Pharmacia), New Jersey Piscataway) of 10 units, and 25 ℃ of incubations 2 hours.Use Benzamidine-Sepharose 6B (Pharmacia (Pharmacia), New Jersey Piscataway) to remove zymoplasm in batches.Albumen is concentrated and dialysis.This albumen is used for coactivator peptide supplementary test (coactivator peptide recruitment assay).
Anti--six His antibody of europium-conjugated and APC-conjugated chain bacterium antibiotin are available from PerkinElmer Life and Analytical Sciences.
TR β/RXR/GRIP coactivator peptide supplementary test
With 30 microlitres at 50mM Hepes, pH7.0,1mM DTT, the H6-TR β (50nM) among 0.05%NP40 and the 0.2mg/ml BSA (binding buffer liquid) mixes with isopyknic EE-RxR α (50nM) in binding buffer liquid.The T3 in DMSO (0-14.8uM) or the test compounds (0-1.2mM) that add 6 microlitres then, and with solution at 37 ℃ of incubation 30min.The binding buffer liquid that is added in 30ul then add 30 microlitres vitamin H-GRIP peptide among the 5%DMSO (vitamin H-Aca-HGTSLKEKHKILHRLLQDSSSPVDL-CONH2) (100nM), and with solution at 37 ℃ of incubation 30min.Add 30 microlitres at 50mM Tris, pH7.4 contains the solution of anti--six His antibody of 12nM europium-conjugated and 160nM APC-conjugated chain bacterium antibiotin among 100mM NaCl and the 0.2mg/ml BSA, and solution is incubated overnight at 4 ℃.Aliquots containig (35ul/ sample) is transferred on the black microtiter plate in 384 holes.On Victor5 reader (PerkinElmer Lifeand Analytical Sciences), read the HTRF signal.
TR α/RXR/GRIP coactivator peptide supplementary test
Experimental draft is substantially the same with above-mentioned TR β/RXR/GRIP coactivator peptide supplementary test, and difference is to use the H6-TR α of 125nM, the EE-RxR α of 125nM and vitamin H-GRIP of 250nM.
As shown in the table, the compound of test is a thyroid hormone receptor agonists, from the EC of THR-β/RXR/GRIP supplementary test
50Value is:
| Embodiment | THR-β/RXR/GRIP supplementary test EC 50(μM) | Systematic name |
| Embodiment 1 | 7.745 | [4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-3,5-dimethyl-phenyl]-acetate |
| Embodiment 2 | 7.31 | [3-chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-5-methyl-phenyl]-acetate (10b) |
| Embodiment 3 | 0.51875 | [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-benzene |
| Embodiment | THR-β/RXR/GRIP supplementary test EC 50(μM) | Systematic name |
| Base]-acetate | ||
| Embodiment 4 | 2.33425 | [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate |
| Embodiment 5 | 0.699 | 3-[3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-propionic acid |
| Embodiment 6 | 0.666 | [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl amino]-acetate |
| Embodiment 7 | 0.117 | N-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-oxalic acid |
| Embodiment 8 | 0.1918 | 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile |
| Embodiment 9 | 0.115 | 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-2H-[1,2,4] triazine-3, the 5-diketone |
| Embodiment 10 | 0.767 | [3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate |
| Embodiment 11 | 1.2 | Synthetic [3,5-two bromo-4-(1-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate |
| Embodiment | THR-β/RXR/GRIP supplementary test EC 50(μM) | Systematic name |
| Embodiment 12 | 0.133 | 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile |
| Embodiment 13 | 0.092 | 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-[1,2,4] triazine-3, the 5-diketone |
| Embodiment 14 | 2.99 | [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate |
| Embodiment 15 | 0.601 | [3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate |
| Embodiment 16 | 0.066 | 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene [1,2,4] triazine-6-nitrile |
| Embodiment 17 | 2.04 | [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-acetate |
| Embodiment 18 | 9.178 | [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-sulfinyl)-phenyl]-acetate |
| Embodiment 19 | 6.98 | [3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-acetate |
| Embodiment 20 | 7.04 | 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxygen |
| Embodiment | THR-β/RXR/GRIP supplementary test EC 50(μM) | Systematic name |
| Generation-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile | ||
| Embodiment 21 | 3.21 | 2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-2H-[1,2,4] triazine-3, the 5-diketone |
| Embodiment 22 | 0.136 | 2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile |
Should be appreciated that to the invention is not restricted to above-mentioned specific embodiments of the present invention, because can carry out the variation of specific embodiments, and they still fall in the scope of appended claim book.
Embodiment A
The film coating tablet that can contain following composition with the usual manner manufacturing:
Composition
Every
Nuclear:
Formula (I) compound 10.0mg 200.0mg
Microcrystalline Cellulose 23.5mg 43.5mg
Lactose hydrate 60.0mg 70.0mg
Polyvinylpyrrolidone K30 12.5mg 15.0mg
Primojel 12.5mg 17.0mg
Magnesium Stearate 1.5mg 4.5mg
(nuclear is heavy) 120.0mg 350.0mg
Film coating:
Vltra tears 3.5mg 7.0mg
Polyethylene glycol 6000 0.8mg 1.6mg
Talcum 1.3mg 2.6mg
Ferric oxide (Huang) 0.8mg 1.6mg
Titanium dioxide 0.8mg 1.6mg
Activeconstituents is sieved also and the Microcrystalline Cellulose mixing, use the polyvinylpyrrolidone aqueous solution mixture pelleting.Particle is mixed with primojel and Magnesium Stearate and compress, obtain weighing respectively 120 or the nuclear of 350mg.Should examine with above-mentioned film-coated aqueous solution/suspension and apply.
Embodiment B
The capsule that can contain following composition with the usual manner manufacturing:
Composition
Each capsule
Formula (I) compound 25.0mg
Lactose 150.0mg
W-Gum 20.0mg
Talcum 5.0mg
Described component is sieved and mix, in No. 2 capsules of packing into then.
Embodiment C
Injection liquid can have following composition:
Formula (I) compound 3.0mg
Poly(oxyethylene glycol) 400 150.0mg
Acetate is in right amount to pH5.0
The injection liquid water is supplied 1.0ml
Activeconstituents is dissolved in the mixture of poly(oxyethylene glycol) 400 and water for injection (part).With acetate pH is transferred to 5.0.The water that adds surplus is transferred to 1.0ml with volume.Use suitably this excessive solution, with its filtration, also sterilization in the bottle of packing into.
Embodiment D
The soft gelatin capsule that can contain following composition with the usual manner manufacturing:
Capsule 's content
Formula (I) compound 5.0mg
Yellow wax 8.0mg
Hydrogenated soybean oil 8.0mg
Partially hydrogenated vegetables oil 34.0mg
Soybean oil 110.0mg
Capsule 's content weight 165.0mg
Gelatine capsule
Gelatin 75.0mg
Glycerine 85% 32.0mg
Karion 83 8.0mg (dry-matter)
Titanium dioxide 0.4mg
Iron oxide yellow 1.1mg
Activeconstituents is dissolved in the warm molten mass of other composition, mixture is packed in the soft gelatin capsule of suitable size.Soft gelatin capsule after filling is handled according to common program.
Embodiment E
The sachet that can contain following composition with the usual manner manufacturing:
Formula (I) compound 50.0mg
Lactose, fine powder 1015.0mg
Microcrystalline Cellulose (AVICEL PH 102) 1400.0mg
Xylo-Mucine 14.0mg
Polyvinylpyrrolidone K30 10.0mg
Magnesium Stearate 10.0mg
Odor additive 1.0mg
Activeconstituents is mixed with lactose, Microcrystalline Cellulose and Xylo-Mucine, and with the mixed solution of polyvinylpyrrolidone and water with its granulation.Particle is mixed with Magnesium Stearate and odor additive, and in the sachet of packing into.
Claims (32)
1. formula (I) compound:
Wherein:
A is O, CH
2, S, SO or SO
2
X and Y be selected from independently of one another Br, Cl and-CH
3
R
1Be selected from:
-(CH
2)
nCOOH；
-OCH
2COOH；
-NHC(＝O)COOH；
-NHCH
2COOH；
Z is H, or-C ≡ N;
R
2It is low alkyl group;
R
3Be H or low alkyl group;
N is 1,2 or 3;
P is 1 or 2;
Or its medicinal salt or ester.
2. according to the compound of claim 1, each Br naturally of X and Y wherein.
3. according to the compound of claim 1, each Cl naturally of X and Y wherein.
4. according to the compound of claim 1, wherein X and Y each naturally-CH
3
5. according to the compound of claim 1, wherein X is Cl, and Y is-CH
3
6. according to the compound of claim 1, R wherein
1Be selected from:
-(CH
2)
nCOOH；
-OCH
2COOH；
-NHC (=O) COOH; With
-NHCH
2COOH; And their ester.
7. according to the compound of claim 6, R wherein
1Be-(CH
2)
nCOOH.
8. according to the compound of claim 7, wherein n is 1.
9. according to the compound of claim 6, R wherein
1Be-NHC (=O) COOH.
10. according to the compound of claim 1, R wherein
1Be:
11. according to the compound of claim 10, wherein R
1Be
12. according to the compound of claim 11, wherein Z is CN.
13. according to the compound of claim 1, wherein R
2It is the low alkyl group that contains 1 to 3 C atom.
14. according to the compound of claim 11, wherein R
2It is the low alkyl group that contains 3 C atoms.
15. according to the compound of claim 1, wherein R
3Be CH
3
16. according to the compound of claim 1, this compound is
Or its medicinal salt or ester.
17. according to the compound of claim 1, this compound is
Or its pharmaceutical salts.
18. according to the compound of claim 1, this compound is
Or its medicinal salt or ester.
19. according to the compound of claim 1, this compound is
Or its medicinal salt or ester.
20. according to the compound of claim 1, this compound is
Or its medicinal salt or ester.
21. according to the compound of claim 2, this compound is
Or its medicinal salt or ester.
22. according to the ester of the compound of claim 6, it has corresponding to R
1Ester group, described ester group is-(=O) COOR, wherein the ester group corresponding to described " R " is NH to NHC
2
23. according to the compound of claim 1, it is selected from:
[4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-3,5-dimethyl-phenyl]-acetate,
[3-chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-5-methyl-phenyl]-acetate,
[3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate,
[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate,
3-[3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-propionic acid,
[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl amino]-acetate,
N-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-the oxalyl amino acid,
2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile,
2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-2H-[1,2,4] triazine-3, the 5-diketone,
[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate,
[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-acetate,
2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile,
2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-[1,2,4] triazine-3, the 5-diketone,
[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate,
[3,5-two bromo-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-acetate,
2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-base oxygen base)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene [1,2,4] triazine-6-nitrile,
[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-base sulfenyl)-phenyl]-acetate,
[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-sulfinyl)-phenyl]-acetate,
[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-acetate,
2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile,
2-[3,5-two chloro-4-(5-sec.-propyl-6-oxo-1,6-dihydro-pyridazine-3-alkylsulfonyl)-phenyl]-2H-[1,2,4] triazine-3, the 5-diketone and
2-[3,5-two chloro-4-(5-sec.-propyl-1-methyl-6-oxo-1,6-dihydro-pyridazine-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydrochysene-[1,2,4] triazine-6-nitrile,
Or its medicinal salt or ester.
24. pharmaceutical composition, it comprises according to each compound and pharmaceutical carrier and/or assistant agent among the claim 1-23.
25. as therapeutic active substance according to each compound among the claim 1-23.
26. as therapeutic active substance according to each compound among the claim 1-23, it is used for the treatment of and/or prevent disease by the thyroid hormone analogs adjusting.
27. one kind is used for the treatment of and/or the method for prophylactic treatment disease, described disease is regulated by thyroid hormone analogs, metabolic trouble particularly, as obesity, hyperlipidaemia, hypercholesterolemia and diabetes, and NASH (NA fatty liver), atherosclerosis, cardiovascular disorder, hypothyroidism, thyroid carcinoma and associated conditions and disease, this method comprise with according to each compound among the claim 1-23 to human or animal's administration.
28. according to each application of compound among the claim 1-23, the disease that it is used for the treatment of and/or prophylactic treatment is regulated by thyroid hormone analogs.
29. according to each application of compound among the claim 1-23, it is used for the treatment of and/or prophylactic treatment metabolic trouble, obesity, hyperlipidaemia, hypercholesterolemia, diabetes, NASH (NA fatty liver), atherosclerosis, cardiovascular disorder, hypothyroidism, thyroid carcinoma and associated conditions and disease.
30. according to each application of compound among the claim 1-23, it is used to prepare and is used for the treatment of and/or the medicine of the disease that prophylactic treatment is regulated by thyroid hormone analogs.
31. according to each application of compound among the claim 1-23, it is used to prepare medicine, and described medicine is used for the treatment of and/or prophylactic treatment metabolic trouble, obesity, hyperlipidaemia, hypercholesterolemia, diabetes, NASH (NA fatty liver), atherosclerosis, cardiovascular disorder, hypothyroidism, thyroid carcinoma and associated conditions and disease.
32. the present invention as defined above.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US70121505P | 2005-07-21 | 2005-07-21 | |
| US60/701,215 | 2005-07-21 | ||
| PCT/EP2006/064093 WO2007009913A1 (en) | 2005-07-21 | 2006-07-11 | Pyridazinone derivatives as thyroid hormone receptor agonists |
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|---|---|
| CN101228135A true CN101228135A (en) | 2008-07-23 |
| CN101228135B CN101228135B (en) | 2011-08-31 |
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| JP (1) | JP5000649B2 (en) |
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| CN (1) | CN101228135B (en) |
| AR (1) | AR054848A1 (en) |
| AT (1) | ATE480524T1 (en) |
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| CA (1) | CA2614529C (en) |
| CR (1) | CR9644A (en) |
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| WO2021164718A1 (en) * | 2020-02-20 | 2021-08-26 | 昆药集团股份有限公司 | 2,6-disubstituted 1,2,4-triazine-3,5-dione compound, and preparation method therefor, and application thereof |
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| WO2022052822A1 (en) * | 2020-09-10 | 2022-03-17 | 苏州科睿思制药有限公司 | Crystal form of resmetirom, preparation method therefor, and use thereof |
| WO2022127779A1 (en) | 2020-12-17 | 2022-06-23 | 山东第一医科大学(山东省医学科学院) | Substituted pyridazinone compound and use thereof |
| GB2608781B (en) * | 2020-12-17 | 2023-07-05 | Shandong First Medical Univ & Shandong Academy Of Medical Sciences | Substituted pyridazinone compound and use thereof |
| GB2608781A (en) * | 2020-12-17 | 2023-01-11 | Shandong First Medical Univ & Shandong Academy Of Medical Sciences | Substituted pyridazinone compound and use thereof |
| CN112645936B (en) * | 2020-12-17 | 2022-03-01 | 山东第一医科大学(山东省医学科学院) | Substituted pyridazinone compound and use thereof |
| AU2021402802B2 (en) * | 2020-12-17 | 2023-11-23 | Shandong First Medical University & Shandong Academy Of Medical Sciences | Substituted pyridazinone compound and use thereof |
| KR102651280B1 (en) | 2020-12-17 | 2024-03-26 | 산동 퍼스트 메디컬 유니버시티 앤드 산동 아카데미 오브 메디컬 사이언시스 | Substituted pyridazinone compounds and their uses |
| US11964962B2 (en) | 2020-12-17 | 2024-04-23 | Shandong First Medical University & Shandong Academy Of Medical Sciences | Substituted pyridazinone compound and use thereof |
| KR20220143775A (en) * | 2020-12-17 | 2022-10-25 | 산동 퍼스트 메디컬 유니버시티 앤드 산동 아카데미 오브 메디컬 사이언시스 | Substituted pyridazinone compounds and their uses |
| CN112645936A (en) * | 2020-12-17 | 2021-04-13 | 山东第一医科大学(山东省医学科学院) | Substituted pyridazinone compound and use thereof |
| WO2022143574A1 (en) * | 2020-12-30 | 2022-07-07 | 昆药集团股份有限公司 | 2-pyridone derivative, and preparation method therefor and pharmaceutical application thereof |
| WO2022171200A1 (en) * | 2021-02-10 | 2022-08-18 | 杭州领业医药科技有限公司 | Resmetirom crystal form, preparation method therefor, and use thereof |
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